Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR2## wherein R 5 , R 6  and R 7  are as defined below, R 2  is C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR3##  wherein R 8 , R 9  and R 10  are as defined below. R 3  is hydrogen, C 1-6  alkyl not containing an asymmetric carbon atom, C 3-7  cycloalkyl or ##STR4##  wherein R 11 , R 12  and R 13  are as defined below, R 4  is hydrogen, C 1-6  alkyl not containing an asymmetric carbon atom, C 7-7  cycloalkyl or ##STR5##  wherein R 14 , R 15  and R 16  are as defined below, X is --(CH 2 ) m  --, --CH═CH--, --CH═CH--CH 2  -- or --CH 2  --CH═CH--, wherein m is 0, 1, 2 or 3, and 
     Z is ##STR6##  wherein R 17  is hydrogen or C 1-3  alkyl, and R 18  is hydrogen, R 19  or M, wherein R 19  is a physiologically acceptable ester group, and 
     M is a pharmaceutically acceptable cation, wherein each of R 5 , R 8 , R 11  and R 14  is independently hydrogen, C 1-3  alkyl, n-butyl, i-butyl, t-butyl, C 1-3  alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R 6 , R 9 , R 12  and R 15  is independently hydrogen, C 1-3  alkyl, C 1-3  alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R 7 , R 10 , R 13  and R 16  is independently hydrogen, C 1-2  alkyl, C 1-2  alkoxy, fluoro or chloro, with the provisos that not more than one substituent on each of Rings A, B, C and D independently is trifluoromethyl, not more than one substituent on each of Rings A, B, C and D independently is phenoxy, and not more than one substituent on each of Rings A, B, C and D independently is benzyloxy, 
     with the provisos that (i) the --X--Z group is in the 2- or 3-position of the pyrrole ring, (ii) the --X--Z group is ortho to both R 1  and R 2 , and (iii) R 3  is ortho to R 2 , the use thereof for inhibiting cholesterol biosynthesis and lowering the blood cholesterol level and, therefore, in the treatment of hyperlipoproteinemia and atherosclerosis, pharmaceutical compositions comprising such compounds and processes for and intermediates in the synthesis of such compounds.

This is a continuation-in-part of application Ser. No. 06/791,198, filedOct. 25, 1985 and now abandoned.

This invention relates to compounds of the formula ##STR7## wherein R₁is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkylor ##STR8## wherein R₅, R₆ and R₇ are as defined below,

R₂ is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇cycloalkyl or ##STR9## wherein R₈, R₉ and R₁₀ are as defined below,

R₃ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom,C₃₋₇ cycloalkyl or ##STR10## wherein R₁₁, R₁₂ and R₁₃ are as definedbelow,

R₄ is hydrogen, C₁₋₆ alkyl not containing an asymmetric carbon atom,C₃₋₇ cycloalkyl or ##STR11## wherein R₁₄, R₁₅ and R₁₆ are as definedbelow,

X is --(CH₂)_(m--), --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--,wherein m is 0, 1, 2 or 3, and ##STR12## wherein R₁₇ is hydrogen or C₁₋₃alkyl, and R₁₈ is hydrogen, R₁₉ or M, wherein R₁₉ is a physiologicallyacceptable ester group, and

M is a pharmaceutically acceptable cation,

wherein each of R₅, R₈, R₁₁ and R₁₄ is independently hydrogen, C₁₋₃alkyl, n-butyl, i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy,trifluoromethyl, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy,each of R₆, R₉, R₁₂ and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy,and each of R₇, R₁₀, R₁₃ and R₁₆ is independently hydrogen, C₁₋₂ alkyl,C₁₋₂ alkoxy, fluoro or chloro, with the provisos that not more than onesubstituent on each of Rings A, B, C and D independently istrifluoromethyl, not more than one substituent on each of Rings A, B, Cand D independently is phenoxy, and not more than one substituent oneach of Rings A, B, C and D independently is benzyloxy, with theprovisos that (i) the --X--Z group is in the 2- or 3-position of thepyrrole ring, (ii) the --X--Z group is ortho to both R₁ and R₂, and(iii) R₃ is ortho to R₂, processes for and intermediates in thesynthesis thereof, pharmaceutical compositions comprising a compound ofFormula I and the use of the compounds of Formula I for inhibitingcholesterol biosynthesis and lowering the blood cholesterol level and,therefore, in the treatment of hyperlipoproteinemia and atherosclerosis.

By the term "physiologically acceptable ester group" is meant a groupwhich, together with the --COO-- radical to which it is attached, formsan ester group which is physiologically acceptable. The preferred suchgroups are the physiologically acceptable and hydrolyzable ester groups.By the term "physiologically acceptable and hydrolyzable ester group" ismeant a group which, together with the --COO-- radical to which it isattached, forms an ester group which is physiologically acceptable andhydrolyzable under physiological conditions to yield a compound ofFormula I wherein R₁₈ is hydrogen and an alcohol which itself isphysiologically acceptable, i.e., non-toxic at the desired dosage level,and which, preferably, is free of centers of asymmetry. Examples of suchgroups are C₁₋₃ alkyl, n-butyl, i-butyl, t-butyl and benzyl,collectively referred to as R₁₉ '.

For the avoidance of doubt, throughout this specification it is theright-hand side of the X radical that is attached to the Z group.

As is self-evident to those in the art, each compound of Formula I (andevery subscope and species thereof) has two centers of asymmetry (thetwo carbon atoms bearing the hydroxy groups in the group of Formula aand the carbon atom bearing the hydroxy group and the carbon atom havingthe free valence in the group of Formula b) and, therefore, there arefour stereoisomeric forms (enantiomers) of each compound (two racematesor pairs of diastereoisomers), provided that R₁₈ does not contain anycenter of asymmetry. The four stereoisomers may be designated as theR,R, R,S, S,R and S,S enantiomers, all four stereoisomers being withinthe scope of this invention. When R₁₈ contains one or more centers ofasymmetry, there are eight or more stereoisomers. Since it is preferredthat R₁₈ not contain a center of asymmetry and for reasons of simplicityany additional stereoisomers resulting from the presence of one or morecenters of asymmetry in R₁₈ usually will be ignored, it being assumedthat R₁₈ is free of centers of asymmetry.

The compounds of Formula I may be divided into two groups, viz., thoseof Formulae IB and IC: ##STR13##

The compounds of each of Groups IB and IC may be divided into twosubgroups based upon the significance of Z, viz., Group IBa (thecompounds of Group IB wherein Z is a group of Formula a), Group IBb (thecompounds of Group IB wherein Z is a group of Formula b), Group ICa (thecompounds of Group IC wherein Z is a group of Formula a) and Group ICb(the compounds of Group IC wherein Z is a group of Formula b).

Preferably, one of R₁ and R₂ is C₁₋₆ alkyl not containing an asymmetriccarbon atom and the other is Ring A (if R₁) or Ring B (if R₂). Alsopreferably, one of R₃ and R₄ is Ring C (if R₃) or Ring D (if R₄) and theother is hydrogen or C₁₋₆ alkyl not containing an asymmetric carbonatom, preferably hydrogen or C₁₋₂ alkyl and most preferably hydrogen,except that R₄ in Formula IC is preferably other than hydrogen. Morepreferably, the preferences of both preceding sentences occursimultaneously. Thus, the preferred compounds of Formula I and each ofthe subscopes thereof are those having attached to the pyrrole ring (i)Ring A or Ring B, (ii) Ring C or Ring D, and (iii) two alkyl groups or,in the case of the compounds of Formula IB, especially one alkyl groupand one hydrogen atom. Even more preferably, Ring A or Ring B, as thecase may be; and Ring C or Ring D, as the case may be, are ortho to eachother.

Also preferably, the pyrrole ring does not bear two ortho tertiary alkylgroups.

In Formula IB:

R₁ is preferably R_(1Bx), where R_(1Bx) is Ring A, more preferably R₁'_(Bx), where R₁ '_(Bx) is Ring A wherein R₅ is R₅ ', R₆ is R₆ ', and R₇is R₇ ', even more preferably R₁ "_(Bx), where R₁ "_(Bx) is Ring Awherein R₅ is R₅ ", R₆ is R₆ ", and R₇ is hydrogen, and most preferablyphenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl;or

R₁ is preferably R_(1By), where R_(1By) is C₁₋₆ alkyl not containing anasymmetric carbon atom, more preferably R₁ '_(By), where R₁ '_(By) isC₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferablyi-propyl.

R₂ is preferably R_(2Bx), where R_(2Bx) is C₁₋₆ alkyl not containing anasymmetric carbon atom, more preferably R₂ '_(Bx), where R₂ '_(Bx) isC₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferablyi-propyl; or

R₂ is preferably R_(2By), where R_(2By) is Ring B, more preferably R₂'_(By), where R₂ '_(By) is Ring B wherein R₈ is R₈ ', R₉ is R₉ ', andR₁₀ is R₁₀ ', even more preferably R₂ "_(By), where R₂ "_(By) is Ring Bwherein R₈ is R₈ ", R₉ is R₉ ", and R₁₀ is hydrogen, and most preferablyphenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl.

R₃ is preferably R_(3Bx), where R_(3Bx) is hydrogen or C₁₋₆ alkyl notcontaining an asymmetric carbon atom, more preferably R₃ '_(Bx), whereR₃ '_(Bx) is hydrogen or C₁₋₂ alkyl, even more preferably R₃ "_(Bx),where R₃ "_(Bx) is hydrogen or methyl, and most preferably hydrogen; or

R₃ is preferably R_(3By), where R_(3By) is Ring C, more preferably R₃'_(By), where R₃ '_(By) is Ring C wherein R₁₁ is R₁₁ ', R₁₂ is R₁₂ ',and R₁₃ is R₁₃ ', even more preferably R₃ "_(By), where R₃ "_(By) isRing C wherein R₁₁ is R₁₁ ", R₁₂ is R₁₂ ", and R₁₃ is hydrogen, and mostpreferably phenyl.

R₄ is preferably R_(4Bx), where R_(4Bx) is Ring D, more preferably R₄'_(Bx), where R₄ '_(Bx) is Ring D wherein R₁₄ is R₁₄ ', R₁₅ is R₁₅ ',and R₁₆ is R₁₆ ', even more preferably R₄ "_(Bx), where R₄ "_(Bx) isRing D wherein R₁₄ is R₁₄ ", R₁₅ is R₁₅ ", and R₁₆ is hydrogen, and mostpreferably phenyl; or

R₄ is preferably R_(4By), where R_(4By) is hydrogen or C₁₋₆ alkyl notcontaining an asymmetric carbon atom, more preferably R₄ '_(By), whereR₄ '_(By) is hydrogen or C₁₋₂ alkyl, even more preferably R₄ "_(By),where R₄ "_(By) is hydrogen or methyl, and most preferably hydrogen.

In Formula IC:

R₁ is preferably R_(1Cx), where R_(1Cx) is C₁₋₆ alkyl not containing anasymmetric carbon atom, more preferably R₁ '_(Cx), where R₁ '_(Cx) isC₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferablyi-propyl; or

R₁ is preferably R_(1Cy), where R_(1Cy) is Ring A, more preferably R₁'_(Cy), where R₁ '_(Cy) is Ring A wherein R₅ is R₅ ', R₆ is R₆ ', and R₇is R₇ ', even more preferably R₁ "_(Cy), where R₁ "_(Cy) is Ring Awherein R₅ is R₅ ", R₆ is R₆ ", and R₇ is hydrogen, and most preferablyphenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl.

R₂ is preferably R_(2Cx), where R_(2Cx) is Ring B, more preferably R₂'_(Cx), where R₂ '_(Cx) is Ring B wherein R₈ is R₈ ', R₉ is R₉ ', andR₁₀ is R₁₀ ', even more preferably R₂ "_(Cx), where R₂ "_(Cx) is Ring Bwherein R₈ is R₈ ", R₉ is R₉ ", and R₁₀ is hydrogen, and most preferablyphenyl, 4-fluorophenyl or 3,5-dimethylphenyl, especially 4-fluorophenyl;or

R₂ is preferably R_(2Cy), where R_(2Cy) is C₁₋₆ alkyl not containing anasymmetric carbon atom, more preferably R₂ '_(Cy), where R₂ '_(Cy) isC₁₋₄ alkyl not containing an asymmetric carbon atom, and most preferablyi-propyl.

R₃ is preferably R_(3Cx), where R_(3Cx) is Ring C, more preferably R₃'_(Cx), where R₃ '_(Cx) is Ring C wherein R₁₁ is R₁₁ ', R₁₂ is R₁₂ ',and R₁₃ is R₁₃ ', even more preferably R₃ "_(Cx), where R₃ "_(Cx) isRing C wherein R₁₁ is R₁₁ ", R₁₂ is R₁₂ ", and R₁₃ is hydrogen, and mostpreferably phenyl; or

R₃ is preferably R_(3Cy), where R_(3Cy) is hydrogen or C₁₋₆ alkyl notcontaining an asymmetric carbon atom, more preferably R₃ '_(Cy), whereR₃ '_(Cy) is hydrogen or C₁₋₂ alkyl, and even more preferably R₃ "_(Cy),where R₃ "_(Cy) is hydrogen or methyl, especially hydrogen.

R₄ is preferably R_(4Cx), where R_(4Cx) is hydrogen or C₁₋₆ alkyl notcontaining an asymmetric carbon atom, more preferably R₄ '_(Cx), whereR₄ '_(Cx) is C₁₋₂ alkyl, and most preferably methyl; or

R₄ is preferably R_(4Cy), where R_(4Cy) is Ring D, more preferably R₄'_(Cy), where R₄ '_(Cy) is Ring D wherein R₁₄ is R₁₄ ', R₁₅ is R₁₅ ',and R₁₆ is R₁₆ ', even more preferably R₄ "_(Cy), where R₄ "_(Cy) isRing D wherein R₁₄ is R₁₄ ", R₁₅ is R₁₅ ", and R₁₆ is hydrogen, and mostpreferably phenyl.

In both formulae:

Each of R₅, R₈, R₁₁ and R₁₄ is preferably R₅ ', R₈ ', R₁₁ ' and R₁₄ ',respectively, where each of R₅ ', R₈ ', R₁₁ ' and R₁₄ ' is independentlyhydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl, fluoro or chloro,and more preferably R₅ ", R₈ ", R₁₁ " and R₁₄ ", respectively, whereeach of R₅ ", R₈ ", R₁₁ " and R₁₄ " is independently hydrogen, methyl orfluoro. R₅ " and R₈ " are most preferably fluoro, especially 4-fluoro,and R₁₁ " and R₁₄ " are most preferably hydrogen.

Each of R₆, R₉, R₁₂ and R₁₅ is preferably R₆ ', R₉ ', R₁₂ ' and R₁₅ ',respectively, where each of R₆ ', R₉ ', R₁₂ ' and R₁₅ ' is independentlyhydrogen, C₁₋₂ alkyl, fluoro or chloro, more preferably R₆ ", R₉ ", R₁₂" and R₁₅ ", respectively, where each of R₆ ", R₉ ", R₁₂ " and R₁₅ " isindependently hydrogen or methyl, and most preferably hydrogen.

Each of R₇, R₁₀, R₁₃ and R₁₆ is preferably R₇ ', R₁₀ ', R₁₃ ' and R₁₆ ',respectively, where each of R₇ ', R₁₀ ', R₁₃ ' and R₁₆ ' isindependently hydrogen or methyl, and most preferably hydrogen.

Preferably, each of Rings A, B, C and D independently bears a maximum ofone substituent selected from the group consisting of t-butyl,trifluoromethyl, phenyl, phenoxy and benzyloxy. More preferably, whenany two or all three of the substituents on Ring A [R₅ (R₅ ', etc.), R₆(R₆ ', etc.) and R₇ (R₇ ', etc.)], Ring B [R₈ (R₈ ', etc.), R₉ (R₉ ',etc.) and R₁₀ (R₁₀ ', etc.)], Ring C [R₁₁ (R₁₁ ', etc.), R₁₂ (R₁₂ ',etc.) and R₁₃ (R₁₃ ', etc.)] and Ring D [R₁₄ (R₁₄ ', etc.), R₁₅ (R₁₅ ',etc.) and R₁₆ (R₁₆ ', etc.)] independently are ortho to each other, atleast one member of each pair that are ortho to each other is a memberof the group consisting of hydrogen, methyl, methoxy, fluoro and chloro.Also more preferably, at least one of the ortho positions of each ofRings A, B, C and D independently has a member of the group consistingof hydrogen, fluoro and methyl.

Each of Rings A and B independently is preferably phenyl, 4-fluorophenylor 3,5-dimethylphenyl, more preferably the latter two and mostpreferably 4-fluorophenyl.

Each of Rings C and D is preferably phenyl.

R₁₇ is preferably R₁₇ ', where R₁₇ ' is hydrogen or methyl, and mostpreferably hydrogen.

R₁₈ is preferably R₁₈ ', where R₁₈ ' is hydrogen, R₁₉ ' or M, morepreferably R₁₈ ", where R₁₈ " is hydrogen, C₁₋₃ alkyl or M, even morepreferably R₁₈ '", where R₁₈ '" is hydrogen, C₁₋₂ alkyl or M, and mostpreferably M, particularly M' and especially sodium.

R₁₉ is preferably a physiologically acceptable and hydrolyzable estergroup, more preferably R₁₉ ', where R₁₉ ' is C₁₋₃ alkyl, n-butyl,i-butyl, t-butyl or benzyl, even more preferably R₁₉ ", where R₁₉ " isC₁₋₃ alkyl, and most preferably R₁₉ '", where R₁₉ '" is C₁₋₂ alkyl,especially ethyl.

Any --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH-- as X is preferablytrans, i.e., (E).

X is preferably X', where X' is --CH₂ CH₂ -- or --CH═CH--, and mostpreferably ##STR14## (i.e., (E) --CH═CH--).

Z is preferably a group of Formula a wherein R₁₇ is R₁₇ ' (especiallyhydrogen), and R₁₈ is R₁₈ ' or a group of Formula b wherein R₁₇ is R₁₇ '(especially hydrogen), more preferably a group of Formula a wherein R₁₇is hydrogen, and R₁₈ is R₁₈ " or a group of Formula b wherein R₁₇ ishydrogen, even more preferably a group of Formula a wherein R₁₇ ishydrogen, and R₁₈ is R₁₈ '" or a group of Formula b wherein R₁₇ ishydrogen, and most preferably a group of Formula a wherein R₁₇ ishydrogen, and R₁₈ is M, preferably M' and especially sodium.

m is preferably m', where m' is 2 or 3, and most preferably 2.

M is preferably free from centers of asymmetry and is more preferablyM', i.e., sodium, potassium or ammonium, and most preferably sodium. Forsimplicity, each formula in which M appears has been written as if Mwere monovalent and, preferably, it is. However, it may also be divalentor trivalent and, when it is, it balances the charge of two or threecarboxy groups, respectively. Thus, Formula I and every other formulacontaining an M embraces compounds wherein M is divalent or trivalent,i.e., compounds containing two or three carboxylate-containing anionsper cation M.

As between otherwise identical compounds of Formula I, those wherein Zis a group of Formula a are generally preferred over those wherein Z isa group of Formula b.

Insofar as the compounds of Groups IBa and ICa and each of the subgroupsthereof are concerned, the erythro isomers are preferred over the threoisomers, erythro and threo referring to the relative positions of thehydroxy groups in the 3- and 5-positions of the group of Formula a.

Insofar as the compounds of Groups IBb and ICb and each of the subgroupsthereof are concerned, the trans lactones are generally preferred overthe cis lactones, cis and trans referring to the relative positions ofR₁₇ and the hydrogen atom in the 6-position of the group of Formula b.

The preferred stereoisomers of the compounds of Formula I having onlytwo centers of asymmetry wherein X is a direct bond, --CH═CH-- or --CH₂--CH═CH--, and Z is a group of Formula a are the 3R,5S isomer and theracemate of which it is a constituent, i.e., the 3R,5S-3S,5R (erythro)racemate.

The preferred stereoisomers of the compounds of Formula I having onlytwo centers of asymmetry wherein X is --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂CH₂ -- or --CH═CH--CH₂ --, and Z is a group of Formula a are the 3R,5Risomer and the racemate of which it is a constituent, i.e., the3R,5R-3S,5S (erythro) racemate.

The preferences set forth in the preceding two paragraphs also apply tothe compounds of Formula I having more than two centers of asymmetry andrepresent the preferred configurations of the indicated positions.

The preferred stereoisomers of the compounds of Formula I wherein X is adirect bond, --CH═CH-- or --CH₂ --CH═CH--, and Z is a group of Formula bare the 4R,6S and 4R,6R isomers and the racemate of which each is aconstituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,6R-4S,6S (cislactone) racemates, with the 4R,6S isomer and the racemate of which itis a constituent being more preferred.

The preferred stereoisomers of the compounds of Formula I wherein X is--CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ -- or --CH═CH--CH₂ --, and Z is agroup of Formula b are the 4R,6R and 4R,6S isomers and the racemate ofwhich each is a constituent, i.e., the 4R,6R-4S,6S (trans lactone) and4R,6S-4S,6R (cis lactone) racemates, with the 4R,6R isomer and theracemate of which it is a constituent being more preferred.

Each of the preferences set forth above applies, not only to thecompounds of Formula I, but also to the compounds of Formulae IB and ICand those of Groups IBa, IBb, ICa and ICb as well as to every othersubgroup thereof set forth in the specification, e.g., Groups (i) etseq., unless otherwise indicated. When any preference or group containsa variable, the preferred significances of that variable apply to thepreference or group in question, unless otherwise indicated.

Preferred groups of compounds of Groups IBa, IBb, ICa and ICb includethe compounds

(i) of Group IBa wherein R₁ is R_(1Bx), R₂ is R_(2Bx), R₃ is R_(3Bx), R₄is R_(4Bx), R₁₇ is R₁₇ ', R₁₈ is R₁₈ ', and X is X',

(ii) of (i) wherein R₁ is R₁ '_(Bx), R₂ is R₂ '_(Bx), R₃ is R₃ '_(Bx),R₄ is R₄ '_(Bx), R₁₇ is hydrogen, R₁₈ is R₁₈ ", and X is (E)--CH═CH--,

(iii) of (ii) wherein R₁ is R₁ "_(Bx), R₃ is R₃ "_(Bx), R₄ is R₄ "_(Bx),and R₁₈ is R₁₈ '", preferably M,

(iv) of Group IBa wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3By),R₄ is R_(4By), R₁₇ is R₁₇ ', R₁₈ is R₁₈ ', and X is X',

(v) of (iv) wherein R₁ is R₁ '_(By), R₂ is R₂ '_(By), R₃ is R₃ '_(By),R₄ is R₄ '_(By), R₁₇ is hydrogen, R₁₈ is R₁₈ ", and X is (E)--CH═CH--,

(vi) of (v) wherein R₂ is R₂ "_(By), R₃ is R₃ "_(By), R₄ is R₄ "_(By),and R₁₈ is R₁₈ '", preferably M,

(vii) of Group IBa wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3Bx),R₄ is R_(4Bx), R₁₇ is R₁₇ ', R₁₈ is R₁₈ ', and X is X',

(viii) of (vii) wherein R₁ is R₁ '_(By), R₂ is R₂ '_(By), R₃ is R₃'_(Bx), R₄ is R₄ '_(Bx), R₁₇ is hydrogen, R₁₈ is R₁₈ ", and X is(E)--CH═CH--,

(ix) of (viii) wherein R₂ is R₂ "_(By), R₃ is R₃ "_(Bx), R₄ is R₄"_(Bx), and R₁₈ is R₁₈ '", preferably M,

(x)-(xviii) of (i)-(ix) wherein the hydroxy groups in the 3- and5-positions of the group of Formula a have the erythro configuration,

(xix) of Group IBb wherein R₁ is R_(1Bx), R₂ is R_(2Bx), R₃ is R_(3Bx),R₄ is R_(4Bx), R₁₇ is R₁₇ ', and X is X',

(xx) of (xix) wherein R₁ is R₁ '_(Bx), R₂ is R₂ '_(Bx), R₃ is R₃ '_(Bx),R₄ is R₄ '_(Bx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxi) of (xx) wherein R₁ is R₁ "_(Bx), R₃ is R₃ "_(Bx), and R₄ is R₄"_(Bx),

(xxii) of Group IBb wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3By),R₄ is R_(4By), R₁₇ is R₁₇ ', and X is X',

(xxiii) of (xxii) wherein R₁ is R₁ '_(By), R₂ is R₂ '_(By), R₃ is R₃'_(By), R₄ is R₄ '_(By), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxiv) of (xxiii) wherein R₂ is R₂ "_(By), R₃ is R₃ "_(By), and R₄ is R₄"_(By),

(xxv) of Group IBb wherein R₁ is R_(1By), R₂ is R_(2By), R₃ is R_(3Bx),R₄ is R_(4Bx), R₁₇ is R₁₇ ', and X is X',

(xxvi) of (xxv) wherein R₁ is R₁ '_(By), R₂ is R₂ '_(By), R₃ is R₃'_(Bx), R₄ is R₄ '_(Bx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(xxvii) of (xxvi) wherein R₂ is R₂ "_(By), R₃ is R₃ "_(Bx), and R₄ is R₄"_(Bx),

(xxviii)-(xxxvi) of (xix)-(xxvii) wherein R₁₇ and the hydrogen atom inthe 6-position of the group of Formula b are trans to each other, i.e.,the trans lactones,

(xxxvii) of Group ICa wherein R₁ is R_(1Cx), R₂ is R_(2Cx), R₃ isR_(3Cx), R₄ is R_(4Cx), R₁₇ is R₁₇ ', R₁₈ is R₁₈ ', and X is X',

(xxxviii) of (xxxvii) wherein R₁ is R₁ '_(Cx), R₂ is R₂ '_(Cx), R₃ is R₃'_(Cx), R₄ is R₄ '_(Cx), R₁₇ is hydrogen, R₁₈ is R₁₈ ", and X is(E)--CH═CH--,

(xxxix) of (xxxviii) wherein R₂ is R₂ "_(Cx), R₃ is R₃ "_(Cx), R₄ ismethyl, and R₁₈ is R₁₈ '", preferably M,

(xl) of Group ICa wherein R₁ is R_(1Cy), R₂ is R_(2Cy) ; R₃ is R_(3Cy),R₄ is R_(4Cy), R₁₇ is R₁₇ ', R₁₈ is R₁₈ ', and X is X',

(xli) of (xl) wherein R₁ is R₁ '_(Cy), R₂ is R₂ '_(Cy), R₃ is R₃ '_(Cy),R₄ is R₄ '_(Cy), R₁₇ is hydrogen, R₁₈ is R₁₈ ", and X is (E)--CH═CH--,

(xlii) of (xli) wherein R₁ is R₁ "_(Cy), R₃ is R₃ "_(Cy), R₄ is R₄"_(Cy), and R₁₈ is R₁₈ '", preferably M,

(xliii)-(xlviii) of (xxxvii)-(xlii) wherein the hydroxy groups in the 3-and 5-positions of the group of Formula a have the erythroconfiguration,

(xlix) of Group ICb wherein R₁ is R_(1Cx), R₂ is R_(2Cx), R₃ is R_(3Cx),R₄ is R_(4Cx), R₁₇ is R₁₇ ', and X is X',

(l) of (xlix) wherein R₁ is R₁ '_(Cx), R₂ is R₂ '_(Cx), R₃ is R₃ '_(Cx),R₄ is R₄ '_(Cx), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(li) of (l) wherein R₂ is R₂ "_(Cx), R₃ is R₃ "_(Cx), and R₄ is methyl,

(lii) of Group ICb wherein R₁ is R_(1Cy), R₂ is R_(2Cy), R₃ is R_(3Cy),R₄ is R_(4Cy), R₁₇ is R₁₇ ', and X is X',

(liii) of (lii) wherein R₁ is R₁ '_(Cy), R₂ is R₂ '_(Cy), R₃ is R₃'_(Cy), R₄ is R₄ '_(Cy), R₁₇ is hydrogen, and X is (E)--CH═CH--,

(liv) of (liii) wherein R₁ is R₁ "_(Cy), R₃ is R₃ "_(Cy), and R₄ is R₄"_(Cy), and

(lv)-(lx) of (xlix)-(liv) wherein R₁₇ and the hydrogen atom in the6-position of the group of Formula b are trans to each other, i.e., thetrans lactones.

Groups (x)-(xviii) and (xliii)-(xlviii) embrace the 3R,5S-3S,5R racemateand the 3R,5S and 3S,5R enantiomers of the compounds wherein X is--CH═CH--, the 3S,5R enantiomer being least preferred, and the3R,5R-3S,5S racemate and the 3R,5R and 3S,5S enantiomers of thecompounds wherein X is --CH₂ CH₂ --, the 3S,5S enantiomer being leastpreferred.

Groups (xxviii)-(xxxvi) and (lv)-(lx) embrace the 4R,6S-4S,6R racemateand the 4R,6S and 4S,6R enantiomers of the compounds wherein X is--CH═CH--, the 4S,6R enantiomer being least preferred, and the4R,6R-4S,6S racemate and the 4R,6R and 4S,6S enantiomers of thecompounds wherein X is --CH₂ CH₂ --, the 4S,6S enantiomer being leastpreferred.

Other representative groups of compounds are (1)-(3) those of FormulaeI, IB and IC wherein each of R₆, R₉, R₁₂ and R₁₅ is other than bromo and(4)-(23) those of Groups (i), (iv), (vii), (x), (xiii), (xvi), (xix),(xxii), (xxv), (xxviii), (xxxi), (xxxiv), (xxxvii), (xl), (xliii),(xlvi), (xlix), (lii), (lv) and (lviii) wherein each of R₆, R₉, R₁₂ andR₁₅ is other than bromo.

The compounds of Formula I may be synthesized as follows:

Reaction Scheme I

The compounds of Formula I wherein X is --(CH₂)_(m) -- or (E)--CH═CH--,and Z is a group of Formula a wherein R₁₇ is hydrogen, and R₁₈ is R₁₉ 'or R₁₇ is R_(17a) and R₁₈ is M₂.sup.⊕ or R₂₀ may be synthesized by thefollowing series of reactions: ##STR15##

Reaction Scheme II

The compounds of Formula I wherein X is --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --,--CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, and Z is a group ofFormula a wherein R₁₈ is R₁₉ ' may be synthesized by the followingseries of reactions: ##STR16##

Reaction Scheme III

The compounds of Formula I wherein X is --CH═CH-- or --CH₂ --CH═CH--,and Z is a group of Formula b having the 4R,6S configuration or X is--CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, and Z is a group of Formula b havingthe 4R,6R configuration may be synthesized by the following series ofreactions: ##STR17##

Reaction Scheme IV

The compounds of Formula I wherein Z is a group of Formula a wherein R₁₈is R₁₉ ' or a group of Formula b may be converted into the correspondingcompounds of Formula I wherein Z has a different significance by thefollowing series of reactions: ##STR18##

Reaction Scheme V

The compounds of Formula VI may be synthesized by the following seriesof reactions: ##STR19##

Reaction Scheme VI

The compounds of Formulae XIX and XX may be synthesized by the followingseries of reactions: ##STR20##

Reaction Scheme VII

The compounds of Formula XLI wherein Pr is PrB wherein R₄ is R_(4a) maybe synthesized by the following series of reactions: ##STR21##

In the preceding reaction schemes, ##STR22## wherein R₁ -R₄ are asdefined above, ##STR23## wherein R₁ -R₄ are as defined above, and R_(4a)and R₂₀ are as defined below, ##STR24## wherein R₁ -R₄ as as definedabove, and R_(4a) and R₃₄ -R₃₆ are as defined below,

R_(4a) is C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇cycloalkyl ##STR25## wherein R₁₄ -R₁₆ are as defined above,

R_(17a) is C₁₋₃ alkyl,

each R₂₀ is independently C₁₋₃ alkyl, preferably n-C₁₋₃ alkyl, and mostpreferably C₁₋₂ alkyl,

each R₂₁ is independently C₁₋₂ alkyl, the two C₁₋₂ alkyl groupspreferably being the same,

each of R₃₄ and R₃₅ is independently C₁₋₆ alkyl not containing anasymmetric carbon atom, preferably methyl,

R₃₆ is C₁₋₆ alkyl not containing an asymmetric carbon atom, preferablymethyl or t-butyl and especially t-butyl,

X₁ is --(CH₂)_(m) -- or (E)--CH═CH--, especially (E)--CH═CH--, wherein mis 0, 1, 2 or 3,

X₂ is --CH₂ -- or --CH₂ CH₂ --,

X₃ is a direct bond or --CH₂ --,

X₄ is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--, preferably(E)--CH═CH--, (E)--CH═CH--CH₂ -- or (E)--CH₂ --CH═CH-- and especially(E)--CH═CH--,

X₅ is --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, especially --CH₂ CH₂ --,

X₆ is --CH═CH-- or --CH₂ --CH═CH--, preferably --CH═CH-- and especially(E)--CH═CH--,

Y is chloro, bromo or iodo,

Y.sup.⊖ is chloride, bromide or iodide,

Y' is chloro or bromo,

Y'.sup.⊖ is chloride or bromide,

M₂.sup.⊕ is sodium or potassium, and

each of the other variables is as defined above.

    __________________________________________________________________________                                                             Inert                                                                         Atmos-               Reaction/Type                                                                         Reagents, Molar Ratios and Comments                                                                 Temperature                                                                             Time    Solvent  phere                __________________________________________________________________________    A       1 Generation of dianion of VII:                                                                     -50°-10° C.,                                                              0.5-3 hrs.                                                                            AIO, e.g.,                                                                             Yes                          2-2.4 equivalents strong base,                                                                      pref. -20°-5° C.                                                                  pref. THF                                                                              (pref.                       pref. 1-1.1 moles sodium hydride then            argon)                       1-1.1 moles  -n-butyllithium or 2-2.2 moles                                   lithium diisopropylamide per mole VII.                                        2 1-2.5 moles, pref. 1.2-2.2 moles, more                                                            -80°-0° C.,                                                               0.2-4 hrs.,                                                                           Same as Step                                                                           Yes                          pref. 1.3-2.1 moles, dianion of VII                                                                 -50°-0° C.,                                                               pref. 0.3-       (pref.                       (assuming 100% conversion of VII to its                                                             pref. -30°-                                                                      2.5 hrs.         argon)                       dianion) per mole VI. When Pr is PrC                                                                -10° C.                                          wherein R.sub.4 is hydrogen, use extra equiva-                                lent of dianion, i.e., 2-3.5 moles, pref.                                     2.2-3.2 moles and more pref. 2.3-3.1                                          moles, per mole VI.                                                           3 Quench with, e.g., saturated ammonium                                                             Same as Step 2                                                                          1-5 min.                                                                              Same as Step                                                                           --                           chloride solution.                                                            Product (VIII) is racemic.                                            B (Reduction)                                                                         a Non-stereoselective: 1-4, pref. 2-4,                                                              -10°-30° C.                                                               1-8 hrs.                                                                              IO, e.g.,                                                                              Yes                          equivalents transferable hydride per    lower alkanol,                        mole VIII, pref. sodium borohydride or  esp. ethanol                          complex of  .sub.-t-butylamine and borane. When                               a racemic VIII is utilized, product                                           (IX) is a mixture of all four possible                                        stereoisomers (the erythro and threo                                          racemates) wherein the ratio of the                                           erythro stereoisomers to the threo stereo-                                    isomers is about 3:2-2:3.                                                     b Stereoselective:                                                            1 1-2.2 moles, pref. 1.02-2 moles, tri-                                                             0°-50° C., pref.                                                          0.5-6 hrs.,                                                                           AIO, pref.                                                                             Pref.                        (primary or secondary C.sub.2 -alkyl)-                                                              0°-25° C.                                                                 pref. 1-3.5                                                                           esp. THF,                                                                              Yes                          borane, pref. triethylborane or tri- -n-                                                                      hrs.    mixture of THF                        butylborane, and, optionally, air,      and methanol,                         e.g., 0.5-8 1., pref. 0.75-6.5 1.,      pref. a 3-4:1                         (at 25° C. and 760 mm. Hg.) per mole                                                                           mixture                               VIII.                                                                 B (Reduction)                                                                         2 0.4-10 moles, pref. 1-10 moles, sodium                                                            -100°- -10° C.,                                                           1-96 hrs.,                                                                            Same as Step                                                                           Pref.                (Cont'd)                                                                              borohydride per mole VIII. After the                                                                pref. -90°-                                                                      pref. 12-72      Yes                          reaction, quench reaction mixture                                                                   -70° C.                                                                          hrs.                                          with, for example, 10% hydrochloric                                           acid and isolate crude product                                                by extracting with a suitable inert                                           organic solvent (e.g., diethyl ether)                                         and evaporating the solvent at reduced                                        pressure. It is pref. to crystallize                                          the cyclic boron ester, if possible.                                          It may be necessary to complete the                                           reaction at -50°- -10° C.                                       3 Large excess of anhydrous methanol,                                                               20°-60° C.                                                                0.5-5 hrs.,                                                                           Neat     --                           e.g., 50-100 moles per mole VIII. It                                                                          pref. 1-4                                     is convenient to azeotrope a solution                                                                         hrs.                                          of the product of Step 2 in methanol                                          three to four times.                                                          When a racemic VIII is utilized in Alter-                                     native b, product (IX) is a mixture of the                                    four possible stereoisomers wherein the                                       ratio of the erythro isomers (racemate) to                                    the threo isomers (racemate) is about 2-20:1,                                 usually 5-15:1, when the solvent is THF.                                      Repeated recrystallization of the cyclic                                      boron ester produced in Step 2 of Alternative                                 b, if a solid, may raise the ratio or even                                    yield pure erythro racemate and mother                                        liquors enriched with threo racemate. When,                                   however, the solvent is a mixture of                                          THF and methanol, said ratio may be as high                                   as 50-100:1.                                                          C       1 Generation of monoanion of X: 1-1.1                                                               -80°- -40° C.,                                                            0.25-1.5                                                                              AIO, e.g.,                                                                             Yes                          equivalents strong base, pref. lithium                                                              pref. -80°-                                                                      hrs.    pref. THF                             diisopropylamide, per mole X.                                                                       -75° C.                                  C       2 1-4 moles, pref. 3 moles, monoanion of                                                            -80°- -40° C.,                                                            0.25-1.5                                                                              Same as Step                                                                           Yes                  (Cont'd)                                                                              X (assuming 100% conversion of X to its                                                             pref. -80°-                                                                      hrs.                                          monoanion) per mole VI. When Pr is PrC                                                              -75° C.                                          wherein R.sub.4 is hydrogen, use extra equiva-                                lent of monoanion, i.e., 2-5 moles, pref.                                     4 moles, monoanion per mole VI.                                               3 Quench with, for example, saturated                                                               -80°-25° C.                                                               1-5 min.                                                                              --       --                           ammonium chloride solution.                                                   Product (XI) is a racemate.                                           D (Acylation)                                                                         1-3 moles, pref. 2 moles, XII or XIII per                                                           -10°-50° C.,                                                              2-18 hrs.,                                                                            Pyridine                                                                               Yes                          mole XI. When an ES is used as the solvent,                                                         pref. 20-30° C.                                                                  pref. 4-12                                                                            anhydrous ES,                         also use 1-4 moles, pref. 2.5-3 moles, of a                                                                   hrs.    pref. THF                             tertiary amine, e.g., pyridine or, pref.,                                     4-dimethylaminopyridine, per mole XI. When                                    Pr is PrC wherein R.sub.4 is hydrogen, use extra                              equivalent of XII or XIII and tertiary amine                                  (when used), e.g., 2-4 moles, pref. 3 moles,                                  XII or XIII per mole XI. Always use at least                                  one mole of tertiary amine (when used) per                                    mole XII or XIII.                                                     E       1 Generation of monoanion of XV: 1-1.1                                                              -80°-0° C.                                                                0.25-1 hr.                                                                            AIO, e.g.,                                                                             Yes                          equivalents strong base, pref. lithium  pref. THF                             diisopropylamide, per mole XV.                                                2 1-4 moles, pref. 3 moles, monoanion of                                                            -80°- -40° C.,                                                            0.25-1.5                                                                              Same as Step                                                                           Yes                          XV (assuming 100% conversion of XV to its                                                           pref. -80°-                                                                      hrs.                                          monoanion) per mole XIV.                                                                            -70° C.                                          3 Quench with, for example, saturated                                                               -80°-25° C.                                                               1-5 min.                                                                              --       --                           ammonium chloride solution.                                           F (Hydrolysis)                                                                        2-2.3 moles, pref. 2-2.2 moles, XVII per                                                            20° C.-reflux,                                                                   2-12 hrs.                                                                             Inert aqueous                                                                          --                           mole XVI. When Pr' contains an R.sub.20 -CO--                                                       pref. 20°-75° C.,                                                         when Pr'                                                                              organic, e.g.,                        group, utilize at least one additional                                                              esp. 50°-75° C.,                                                          contains                                                                              mixture of                            equivalent of XVII, e.g., 3-3.3 moles, pref.                                                        when Pr' con-                                                                           an R.sub.20 --CO--                                                                    water and lower                       3-3.2 moles, XVII per mole XVI.                                                                     tains an R.sub.20 -CO--                                                                 group and,                                                                            alkanol, pref.                                              group and,                                                                              otherwise,                                                                            mixture of                                                  otherwise,                                                                              1-4 hrs.                                                                              water and                                                   0° C.-reflux,                                                                            methanol or,                                                pref. 0°-75° C.,                                                                  esp., ethanol                                               esp. 20°-50° C.                   G (Silylation)                                                                        1-3 moles II per mole XI. When Pr is PrC                                                            20°-30° C.,                                                               6-18 hrs.                                                                             Dry dimethyl-                                                                          Yes                          wherein R.sub.4 is hydrogen, use at least one                                                       20°-25° C.                                                                        formamide                             extra equivalent of II, e.g., 2-4 moles II                                    per mole XI. In either case, also use 1-2                                     moles triethylamine and catalytic amount of                                   imidazole or 1.1-2 moles imidazole per mole                                   II.                                                                   H       Same as Reaction E (Molar quantities in                                                             Same as E Same as E                                                                             Same as                                                                                Yes                          Step 2 are per mole III).                                             HA (Deprotec-                                                                         Same as Reaction J (Molar quantities are per                                                        Same as J Same as J                                                                             Same as                                                                                --                   tion)   mole IV) when Pr" contains an -- SiR.sub.34 R.sub.35 R.sub.36                 group. When Pr" does not contain an                                           --SiR.sub.34 R.sub.35 R.sub.36 group, utilize 1-4 moles, pref.                2-4 moles, fluoride reagent per mole IV.                              I (Wittig)                                                                            Alternative a:                                                                1 1-2 moles strong base, e.g., sodium                                                               -40°-5° C.,                                                               5-60 min.                                                                             AIO, e.g.,                                                                             Yes                          hydride or pref.  -n-butyllithium, per                                                              -35°- -20° C.                                                                     such as toluene                       mole XIX. Pref., slowly add  -n-butyl-  or, pref., ES                         lithium solution to solution of XIX.    such as THF                           When Pr is PrC wherein R.sub.4 is hydrogen, use                               2-3 moles strong base per mole XIX.                                           2 0.65-1.5 moles XXI per mole XIX used in                                                           -55°-25° C.,                                                              0.75-18 Same as Step                                                                           Yes                          Step 1.               pref. -35°-                                                                      hrs., pref.                                                         -5° C.                                                                           1-4 hrs.                              M (Wittig)                                                                            Same as Reaction I. (Reactant in Step 2                                                             Same as I Same as I                                                                             Same as                                                                                Yes                          is XXVI). Product (XXVII) is a mixture of                                     the (Z) and (E) (cis and trans, respectively)                                 isomers which may be separated by chromatog-                                  raphy. The (E) to (Z) ratio may be higher                                     with Alternative b than with Alternative a.                           N (Deprotec-                                                                          Same as Reaction J except utilize 1-4 moles,                                                        Same as J Same as J                                                                             Same as                                                                                --                   tion)   pref. 2-4 moles, fluoride reagent per mole                                    XXVII.                                                                O (Hydrogena-                                                                         Same as Reaction K (Molar quantities are                                                            Same as K Same as K                                                                             Same as                                                                                --                   tion)   per mole XXVII).                                                      P (Deprotec-                                                                          Same as Reaction J except utilize 1-4 moles,                                                        Same as J Same as J                                                                             Same as                                                                                --                   tion)   pref. 2-4 moles, fluoride reagent per mole                                    XXIX.                                                                 Q (Hydrolysis)                                                                        1-1.3 equivalents XVII per mole XXXI or, if                                                         0° C.-reflux,                                                                    1-4 hrs.                                                                              Inert aqueous                                                                          --                           it is desired to isolate XXXII, 0.92-0.99                                                           pref. 0°-75° C.,                                                                  organic, e.g.,                        equivalent XVII per mole XXXI.                                                                      esp. 20°-70° C.                                                                   mixture of                                                                    water and lower                                                               alkanol, pref.                                                                mixture of                                                                    water and                                                                     methanol or,                                                                  esp., ethanol                 R (Acidifica-                                                                         At least 1 equivalent, e.g., 1-1.25 equiv-                                                          0°-25° C.                                                                 1-5 min.                                                                              Water or mix-                 tion)   alents, acid, e.g., 2N. hydrochloric acid,                                                                            ture of water                         per mole XXXII.                         and water-                                                                    miscible or                                                                   partially                                                                     miscible inert                                                                organic sol-                                                                  vent, e.g.,                                                                   methanol,                                                                     ethanol,                                                                      diethyl ether                                                                 or THF                        S (Neutraliza-                                                                        0.95-0.99 equivalent, pref. 0.96-0.98                                                               0°-25° C., pref.                                                          2-10 min.                                                                             Same as                                                                                --                   tion)   equivalent, XXXIV per mole XXXIII.                                                                  20°-25° C.                        T (Lactoniza-                                                                         Alternative a:                                                        tion)                                                                                 Use of catalytic amount of strong acid                                                              75° C.-reflux,                                                                   3-18 hrs.,                                                                            AIO, pref. HC,                        such as  -p-toluenesulfonic acid is optional                                                        pref. 75°-                                                                       pref. 4-7                                                                             e.g., benzene,                        but usually omit. Use of Dean-Stark                                                                 150°  C., esp.                                                                   hrs.    toluene or                            apparatus is pref. if solvent forms                                                                 80°-120° C.                                                                       xylene or                             azeotrope with water.                   mixture                                                                       thereof                               Alternative b:                                                                1-1.5 moles of a lactonization agent,                                                               10°-35° C.,                                                               2-8 hrs.,                                                                             AIO, pref.                            e.g., a carbodiimide, pref. a water-                                                                20°-25° C.                                                                pref. 3-4                                                                             HLA, esp.                             soluble carbodiimide such as N--cyclo-                                                                        hrs.    methylene                             hexyl-N'--[2'-(N"--methylmorpholinium)- chloride                              ethyl] carbodiimide  -p-toluenesulfonate,                                     per mole XXXIII.                                                              Alternative b often results in higher yields                                  of XXXVI than Alternative a. Racemic erythro                                  XXXIII yields racemic trans (lactone) XXXVI,                                  racemic threo XXXIII yields racemic cis                                       (lactone) XXXVI, mixture of racemic erythro                                   and threo XXXIII yields mixture of racemic                                    trans and cis (lactones) XXXVI, and single                                    enantiomer of XXXIII yields single enantiomer                                 of XXXVI, e.g., 3R,5S erythro XXXIII yields                           4R,6S trans XXXVI.                                                            U (Esterifica-                                                                        At least 2 moles, e.g., 2-10 moles, pref.                                                           0°-70° C., pref.                                                          2-12 hrs.                                                                             IO, e.g.,                                                                              --                   tion)   2.05-2.5 moles, XXXVII per mole XXXVI.                                                              20°-25° C.                                                                        such as THF or                                                                alcohol of the                        See comment concerning Reaction V, this formula R.sub.19 -OH                  column.                                 (R.sub.19 same as                                                             in XXXVII), if                                                                a liquid                      V (Hydrolysis)                                                                        1-1.3 equivalents XVII per mole XXXVI or,                                                           0° C.-reflux,                                                                    1-6 hrs.,                                                                             Same as                                                                                --                           if it is desired to isolate XXXII, 0.95-1                                                           pref. 0°-75° C.,                                                          pref. 1-4                                     equivalent, preferably 0.97-0.99 equivalent,                                                        more pref. 20°-                                                                  hrs.                                          XVII per mole XXXVI.  75° C., esp. 40°-                                               60° C.                                           Racemic trans (lactone) XXXVI yields racemic                                  erythro XXXII or XXXVIII, racemic cis                                         (lactone) XXXVI yields racemic threo XXXII                                    or XXXVIII, mixture of racemic trans and                                      cis (lactones) XXXVI yields mixture of                                        racemic erythro and threo XXXII or XXXVIII,                                   and single enantiomer of XXXVI yields single                                  enantiomer of XXXII or XXXVIII, e.g., 4R,6S                                   trans XXXVI yields 3R,5S erythro XXXII or                                     XXXVIII.                                                              AA (Reduction)                                                                        0.5-3.2 moles, pref. 0.75-3 moles, lithium                                                          -5°-25° C.,                                                               2-6 hrs.,                                                                             AIO, e.g.,                                                                             Yes                          aluminum hydride per mole XLI. Pref.                                                                pref. -5°-5° C.→                                                   pref. 2-4                                                                             pref. THF or                          commence at -5°-5° C. and allow reaction                                              20°-25° C. or                                                             hrs.    diethyl ether                         mixture to warm to 20°-25° C. as reaction                                             0°-5° C.                                  proceeds or run entire reaction at 0°-5° C.             AB (Oxidation)                                                                        1-3.5 moles, pref. 1.2-3 moles, pyridinium                                                          20°-30° C.,                                                               2-18 hrs.,                                                                            AIO, pref.                                                                             Yes,                         chlorochromate or pyridinium dichromate,                                                            20°-25° C.                                                                pref. 3-12                                                                            esp. methylene                        5-10 moles, pref. 6-8 moles, chromium                                                                         hrs., with                                                                            chloride, for                         trioxide (pref. complexed with pyridine,                                                                      pyridinium                                                                            pyridinium                            more pref. 2 moles pyridine per mole chrom-                                                                   chloro- chlorochromate,                       ium trioxide), 5-50 moles, pref. 10-20                                                                        chromate or                                                                           chromium                              moles, manganese dioxide, pref. activated                                                                     chromium                                                                              trioxide or                           manganese dioxide, or, pref., 2-4 moles                                                                       trioxide,                                                                             pyridinium                            N--methylmorpholine-N--oxide monohydrate and                                                                  8-24 hrs.,                                                                            dichromate and                        catalytic amount (e.g., 0.02-0.05 mole)                                                                       pref. 15-                                                                             pref. HLA or                          tris(triphenylphosphine)ruthenium (II)                                                                        18 hrs.,                                                                              ES, esp.                              chloride (CXI), per mole XLII.                                                                      with pyri-                                                                              diethyl ether,                                                                dinium  for manganese                                                         dichromate,                                                                           dioxide and                                                           4-48 hrs.,                                                                            dry acetone                                                           pref.   for N--methyl-                                                        10-24 hrs.,                                                                           morpholine-                                                           with    N--oxide                                                              manganese                                                                             monohydrate                                                           dioxide                                                                       and 1-5                                                                       hrs. with                                                                     N--methyl-                                                                    morpholine-                                                                   N--oxide                                                                      monohydrate                           AC (Wittig)                                                                           1 Synthesis of ylide: 1-1.05 moles strong                                                           -40°-0° C.,                                                               1-4 hrs.                                                                              AIO, pref.                                                                             Yes                          base, e.g., sodium hydride, phenyllithium                                                           pref. -35°-                                                                              e.g., THF                             or, pref.,  -n-butyllithium per mole XLIV.                                                          -20° C.                                          Pref., slowly add solution of strong                                          base to solution of XLIV.                                                     2 Synthesis of enol ether: Ylide from                                                               -30°- 0° C.,                                                              1-4 hrs.                                                                              Same as Step                                                                           Yes                          1-1.05 moles XLIV per mole XLIII.                                                                   pref. -20°-0° C.                  AC (Wittig)                                                                           3 Hydrolysis of enol ether: Large molar                                                             0°-30° C.                                                                 8-24 hrs.                                                                             Mixture                                                                                --                   (Cont'd)                                                                              excess, e.g., 2-20 moles, strong acid,  aqueous acid                          e.g., 70% perchloric acid, per mole XLIII                                                                             and ES, e.g.,                         used in Step 2                          mixture of 70%                                                                perchloric                                                                    acid and THF                  AD (Wittig)                                                                           Same as Reaction AC (Molar quantities in                                                            Same as AC                                                                              Same as AC                                                                            Same as                                                                                Same as                      Steps 2 and 3 are per mole XLV).                 AC                   AE (Wittig)                                                                           Same as Reaction AC (Molar quantities in                                                            Same as AC                                                                              Same as AC                                                                            Same as                                                                                Same as                      Steps 2 and 3 are per mole XLVI).                AC                   AF (Wittig)                                                                           Alternative a:                                                                1-2 moles, pref. 1-1.7 moles, XLVIII per                                                            80° C.-reflux,                                                                   6-18 hrs.                                                                             AIO, pref.                                                                             Yes                          mole XLIII.           esp. refluxing    esp. toluene                                                toluene                                                 Alternative b:                                                                1 Synthesis of ylide: 1-1.07 moles strong                                                           -20°-25° C.,                                                              0.75-2 hrs.                                                                           AIO, pref.                                                                             Yes                          base, pref. sodium hydride, per mole                                                                pref. -20°-0° C.                                                                  esp. THF                              XLIX. Pref., add small amount of XLIX                                         to suspension of sodium hydride in THF                                        stirred at 20°-25° C., cool to -20°-                     -15° C.                                                                once reaction commences and complete                                          reaction at -20°- -15° C.                                       2 1-1.6 moles ylide from XLIX (assuming                                                             -20°-65° C.                                                               0.75-20 Same as Step                                                                           Yes                          100% conversion of XLIX to ylide) per                                                                         hrs.                                          mole XLIII. Pref., add solution of XLIII                                      to ylide solution at -20°- -15° C., stir                        at -20°-25° C. for balance of reaction                          and, if necessary, complete reaction at                                       40°-65° C.                                              AG (Reduction)                                                                        1 At least 2 equivalents transferable                                                               -78°-25° C.,                                                              0.7-3 hrs.                                                                            AIO, pref.                                                                             Yes                          hydride from a metal hydride reducing                                                               pref.             e.g., THF                             agent, e.g., lithium aluminum hydride                                                               -78°- -20° C.                             or diisobutylaluminum hydride, per mole                                       L, pref. 3.8-6 moles diisobutylaluminum                                       hydride per mole L.                                                           2 Quench with, for example, water or                                                                -78°-25° C.                                                               5-15 min.                                                                             --       --                           saturated ammonium chloride or sodium                                         sulfate solution.                                                     AH (Oxidation)                                                                        5-50 moles, pref. 10-30 moles, manganese                                                            20° C.-reflux                                                                    3-24 hrs.,                                                                            AIO, pref.                                                                             Yes                          dioxide, pref. activated manganese dioxide,                                                         pref. 20°-40° C.                                                          pref. 10-                                                                             or ES, esp.                                                                            with N-                      or, pref., 2-4 moles N-methylmorpholine-N-                                                          with manganese                                                                          18 hrs. diethyl                                                                                methyl-                      oxide monohydrate and catalytic amount                                                              dioxide and       with manganese                                                                         morpho-                      (e.g., 0.02-0.05 mole) CXI, per mole LI.                                                            20°-25° C. with                                                                   dioxide                                                                                line-                                              N--methyl-        dry acetone                                                                            N-oxide                                            morpholine-       with N--methyl-                                                                        mono-                                              N--oxide          morpholine-                                                                            hydrate                                            monohydrate       N--oxide                                                                      monohydrate                   AI      p Preparation of LIII: 2-2.1 moles, pref.                                                           -80°- -75° C.,                                                            1-5 hrs.,                                                                             AIO, e.g.,                                                                             Yes                          2 moles,  .sub.-t-butyllithium, pref. as 1-2M.                                                      pref. -78° C.                                                                    pref. 2-4                                                                             pref. THF                             solution in pentane, per mole cis-1-bromo-                                                                    hrs.                                          2-ethoxyethylene.                                                     AI      1 1-1.75 moles LIII (assuming 100% yield                                                            -80°- -40 ° C.,                                                           0.75-8 hrs.                                                                           Same as Step                                                                           Yes                  (Cont'd)                                                                              from Step p) per mole XLIII. When Pr                                                                pref. -80°-                                                                      pref. 1-                                      is PrC wherein R.sub.4 is hydrogen, utilize                                                         -60° C.                                                                          4 hrs.                                        an extra equivalent of LIII, i.e., 2-                                         2.75 moles LIII per mole XLIII. When it                                       is desired to isolate and/or purify the                                       crude enol ether intermediate, quench the                                     reaction mixture with, e.g., saturated                                        ammonium chloride solution at -80°- -25° C.                     for 1-5 min. Otherwise, quenching is                                          optional since it will occur at the                                           beginning of Step 2. Crude enol ether                                         product of this step may be used in next                                      step without isolation and purification                                       but isolation and purification of enol                                        ether intermediate may improve yield of                                       LII from next step.                                                   (Hydrolysis)                                                                          2 Catalytic amount of p-toluenesufonic                                                              20°-40° C.,                                                               0.5-5 hrs.,                                                                           Mixture of                                                                             --                           acid or monohydrate thereof (e.g., 0.5-                                                             20°-25° C.                                                                pref. 0.5-                                                                            and water,                            100 g., pref. 1-5 g., per mole XLIII                                                                          4 hrs.  pref. mixture                         used in Step (1) and water.             of THF and                                                                    water                         BA (Halogena-                                                                         1-2 moles, pref. 1.5-1.8 moles, LV or LVI                                                           -10°--80° C.                                                              2-18 hrs.                                                                             AIO, pref.                                                                             --,                  tion)   per mole XLII.                          e.g., diethyl                                                                 ether or THF,                                                                 HLA, e.g.,                                                                    methylene                                                                     chloride, or                                                                  HC, e.g.,                                                                     benzene                       BB      Excess triphenylphosphine, e.g., 2-10 moles                                                         60° C.-reflux,                                                                   0.5-24 hrs.                                                                           AIO, pref.                                                                             Yes                          per mole LVII.        pref. <150° C.,                                                                          absolute                                                    esp. 75°-78° C.                                                                   ethanol                                                     (in absolute                                                                  ethanol)                                        BC      1-1.1 moles LIX per mole LVII. Can use                                                              20°-140° C.,                                                              6-24 hrs.,                                                                            HC, e.g.,                                                                              Yes                          excess LIX as the solvent.                                                                          usually   usually benzene or                                                  110°-140° C.                                                              10-16 hrs.                                                                            xylene or neat                                                                (excess LIX                                                                   is solvent)                   BD      Same as Reaction B, Alternative a (Molar                                                            Same as B, a                                                                            Same as B,                                                                            Same as B,                                                                             Yes                          quantities are per mole XLV).   a                                     BE (Halogena-                                                                         Same as Reaction BA (Molar quantities are                                                           Same as BA                                                                              Same as BA                                                                            Same as                                                                                --                   tion)   per mole LXI).                                                        BF      Same as Reaction BB (Molar quantities are per                                                       Same as BB                                                                              Same as BB                                                                            Same as                                                                                Yes                          mole LXII).                                                           BG      Same as Reaction BC (Molar quantities are                                                           Same as BC                                                                              Same as BC                                                                            Same as                                                                                Yes                          per mole LXII).                                                       CA (Halogena-                                                                         1 mole LXVII per mole LXVI. In this reac-                                                           0°-40° C.                                                                 2-18 hrs.                                                                             AIO, pref.                                                                             --A,                 tion)   tion, LXVII is pref. Br.sub.2.          e.g. chloro-                                                                  form                          CB      1-2 moles triphenylphosphine per mole LXVIII                                                        20°-40° C.,                                                               8-24 hrs.                                                                             AIO, pref.                                                                             Yes                                                20°-25° C.                                                                        or HC, esp.                                                                   toluene                       CC (Wittig)                                                                           1 1-1.02 moles base, e.g., sodium ethoxide,                                                         20°-80° C.                                                                0.25-4 hrs.                                                                           AIO, pref.                                                                             Yes                          per mole LXIX.                          lower alkanol,                                                                esp. ethanol                          2 1-1.25 moles LXX per mole LXIX used in                                                            60°-80° C.                                                                8-24 hrs.                                                                             Same as Step                                                                           Yes                          Step 1.                                                               CD      1 1-1.3 moles base, e.g., sodium hydroxide,                                                         20 °-30° C.                                                               5-15 min.                                                                             Mixture                                                                                --                           per mole LXVI.                          lower alkanol,                                                                pref. ethanol,                                                                water                                 2 1-1.05 moles LXX per mole LXVI. Add LXX                                                           0° 14 5° C.                                                               2-5 hrs.                                                                              Same as Step                                                                           --                           at 0°-5° C. and allow to warm to 20°-25.degre            e. C.                 20°-25° C.                        CE      1 1-1.08 moles strong base, pref. lithium                                                           -80°- -60° C., 0.4-1                                                      AIO, pref. ES,                                                                        Yes                                   diisopropylamide, per mole LXXII.                                                                   pref. -78° C.                                                                            esp. THF                              2 1-1.03 moles carbanion of LXXII (assuming                                                         Same as Step 1                                                                          2-5 hrs.                                                                              Same as Step                                                                           Yes                          100% conversion of LXXII to its carbanion)                                    per mole LXXI.                                                                3 Quench with, for example, saturated                                                               Same as Step 1                                                                          1-5 min.                                                                              Same as Step                                                                           --                           ammonium chloride solution.                                           CF      5.5-6.5 moles, pref. 6 moles, N--bromo-                                                             0° C.                                                                            3-6 hrs.                                                                              Mixture                                                                                --                           succinimide per mole LXXIII.            acetonitrile                                                                  and water,                                                                    pref. a 4:1                                                                   mixture                       CG      1-4 moles, pref. 2-4 moles, LXXV and 0.4-1                                                          0°-120° C.,                                                               12-24 hrs.                                                                            AIO, pref.                                                                             Yes                          mole, pref. 0.6 mole, titanium tetrachloride                                                        pref. 0°→                                                                         esp. mixture                          per mole LXXIV. Pref., combine reactants                                                            111° C.    of hexane and                         at 0° C., allow to warm to 20°-25° C. and                heat                                    toluene                               at 100°-120° C. for 10-22 hrs., e.g., reflux                    in toluene for 16 hrs.                                                __________________________________________________________________________

In the preceding table,

AIO=anhydrous inert organic solvent

ES=ether solvent, for example, diethyl ether, 1,2-diethoxyethane,1,2-dimethoxyethane, tetrahydrofuran and mixtures thereof

esp.=especially

HC=hydrocarbon solvent, for example, benzene, toluene, xylene andmixtures thereof

HLA=halogenated lower alkane solvent, for example, carbon tetrachloride,chloroform, 1,1-dichloroethane, 1,2-dichloroethane, methylene chlorideand 1,1,2-trichloroethane, usually preferably methylene chloride

hr. (hrs.)=hour(s)

IO=inert organic solvent

min.=minutes

pref.=preferably, preferred

THF=tetrahydrofuran

Most of the molar amounts (ratios) given in the preceding table aremerely exemplary and may be varied, as is evident to one of ordinaryskill in the art. For example, in a reaction of two compounds one ofwhich is readily available and one of which isn't, an excess of thereadily available compound may be used to drive the reaction furthertowards completion (unless the use of an excess would increase thesynthesis of an undesired compound).

Likewise, most of the temperature ranges given in the preceding tableare merely exemplary, and it is within the ability of one of ordinaryskill in the art to vary those that are not critical.

The reaction times set forth in the preceding table are also merelyexemplary and may be varied. As is well-known, the reaction time isoften inversely related to the reaction temperature. Generally, eachreaction is monitored by, for example, thin layer chromatography and isterminated when at least one starting material is no longer present,when it appears that no more of the desired product is being formed,etc.

Conventional work-up procedures have generally been omitted from thepreceding table.

As utilized in the preceding table, the term "solvent" embraces mixturesof solvent and implies that the reaction medium is a liquid at thedesired reaction temperature. It should, therefore, be understood thatnot all of the solvents listed for a particular reaction may be utilizedfor the entire recited temperature range. It should also be understoodthat the solvent must be at least substantially inert to the reactantsemployed, intermediates generated and end products under the reactionconditions utilized.

The term "inert atmosphere", as utilized in the preceding table, meansan atmosphere that does not react with any of the reactants,intermediates or end products or otherwise interfere with the reaction.While a carbon dioxide atmosphere is suitable for certain reactions, theinert atmosphere is usually nitrogen, helium, neon, argon or krypton, ora mixture thereof, and most often dry nitrogen to maintain anhydrousconditions. Most reactions, including those where the use of an inertatmosphere is not specified, are carried out under an inert atmosphere,usually dry nitrogen, for convenience.

In the preceding table, n-butyllithium is preferably employed as a1.3-1.7M. solution in hexane, and lithium diisopropylamide is preferablyprepared in situ from n-butyllithium and diisopropylamine.

Reactions analogous to Reactions A-J, L-N, P-V, AA-AH, BA, BB, BD-BF andCB are described in detail in copending application Ser. No. 06/722,288,filed by Faizulla G. Kathawala on Apr. 11, 1985 and title Indole AnalogsOf Mevalonolactone And Derivatives Thereof. These reactions may becarried out analogously to the corresponding reactions of saidapplication. Said application is hereby incorporated by reference.Generally, where the reaction conditions set forth in said applicationdiffer from those set forth in this specification, the reactionconditions set forth in said application may also be utilized for thecompounds of this specification.

The product of each reaction may, if desired, be purified byconventional techniques such as recrystallization (if a solid), columnchromatography, preparative thin layer chromatography, gaschromatography (if sufficiently volatile), fractional distillation underhigh vacuum (if sufficiently volatile) or high pressure (performance)liquid chromatography (HPLC). Often, however, the crude product of onereaction may be employed in the following reaction without purification.

Some of the reactions described above may yield mixtures of two or moreproducts only one of which leads to the desired compound of Formula I.Any obtained mixture may be separated by conventional techniques such asthose set forth in the preceding paragraph.

As is evident to those in the art, each of the compounds of FormulaeIII, VIII, XI and XIV has a single center of asymmetry and, therefore,may be resolved into two optically active isomers. When a compound ofFormula III, VIII or XIV is converted into a compound of Formula IV, IXor XVI, respectively, an additional center of asymmetry is generated.Consequently, when a racemic compound of Formula III, VIII or XIV isutilized, four stereoisomers (two pairs of diastereoisomers) of theresulting compound of Formula IV, IX or XVI are formed, whereas when anoptically pure compound of Formula III, VIII or XIV is utilized, twodiastereoisomers of the compound of Formula IV, IX or XVI are formed.

The compounds of Formulae I (including those of Formulae IB, IC, V,XVIII, XXIII, XXV, etc.), IV, XVI, XXI XXII and XXIV have two centers ofasymmetry and, therefore, may exist in four stereoisomeric forms. Exceptwhere the compound is formed from an optically pure precursor alreadyhaving both chiral carbon atoms or where the reaction involves the useof a stereospecific reagent that gives an optically pure product, thecompound is obtained as a mixture of two (if formed from an opticallypure compound having one center of asymmetry) of four (if formed from aracemic compound having one center of asymmetry) stereoisomers.

The one or two centers of asymmetry of each compound of Formulae LXVIII,LXIX, LXXIII and LXXIV may be ignored since each center of asymmetry isdestroyed in a following reaction (Reaction CG).

The obtained mixtures of stereoisomers may be separated by conventionalmeans. For example, diastereoisomers may be separated by fractionalcrystallization, column chromatography, preparative thin layerchromatography and HPLC. Each mixture of four stereoisomers of acompound of Formula XXXVI may, for example, be separated by HPLC intoits cis and trans (lactone) components, each of which is a racemate thatmay be resolved into two optically active enantiomers.

Techniques for separating a racemate into its two optically activeenantiomers are known. For example, a racemic compound having acarboxylic acid group may be reacted with an optically pure organic basehaving at least one center of asymmetry to form a mixture ofdiastereoisomeric salts that may be separated by fractionalcrystallization, column chromatography, etc. or it may be reacted withan optically pure alcohol having at least one center of asymmetry toform a mixture of diastereoisomeric esters which may be separated byconventional techniques such as those set forth above or below.Likewise, a racemic compound having a carboxylic acid, acyl halide,ester or lactone group may be reacted with an optically pure organicbase, i.e., an amine, to form a mixture of diastereoisomeric amides thatmay be separated by conventional means, e.g., fractionalcrystallization, column chromatography and/or HPLC. For example, aracemic lactone of Formula XXXVI may be reacted with an excess ofR-(+)-α-methylbenzylamine (or the corresponding S-(-) compound) to forma mixture of two diastereoisomeric α-methylbenzylamides which may beseparated by, for example, column chromatography on a silica gel columnand/or by HPLC using a Partisil column. Often it is desirable to utilizeboth techniques, i.e., to partially separate the diastereoisomers bycolumn chromatography and to purify each fraction by HPLC. Typically,the α-methylbenzylamides are synthesized by reacting the racemic lactonewith a large molar excess of the amine at 20°-25° C. for 16-24 hours.The reaction is run neat, with the excess amine serving as the solvent.After the reaction, the excess amine is removed by vacuum distillationat 25°-35° C. After separation, each chiral amide may be hydrolyzed tothe corresponding, for example, sodium, salt by, for example, refluxingwith 1.5-3, preferably 2-2.2, equivalents of a base such as sodiumhydroxide for 5-25 hours in a mixture of water and ethanol. Theresulting salts may be converted to the corresponding free acids, ester,lactones and other salts by conventional means such as the reactions setforth in Reaction Scheme IV. On the other hand, a racemic compoundhaving a hydroxy group may be esterified with an optically purecarboxylic acid having at least one center of asymmetry to form amixture of diastereoisomeric esters or it may be reacted with anoptically pure trisubstituted silyl halide, e.g.,(-)-α-naphthylphenylmethylchlorosilane (Sommer et. al., J. Am. Chem.Soc. 80, 3271 ( 1958).), to form a mixture of two diastereoisomericsilyloxy compounds, which mixture may be separated by conventionaltechniques. For example, diastereoisomeric(-)-α-naphthylphenylmethylsilyl derivatives of a lactone of FormulaXXXVI may be separated on a silica column having covalently boundL-phenylglycine. After separation, the optically pure salts, amides,esters or silyloxy compounds are reconverted to the correspondingcarboxy group- or hydroxy group-containing compounds with retention ofoptical purity. For example, the process conditions disclosed forReactions J, L, N and P may be utilized to cleave(-)-α-naphthylphenylmethylsilyl and other silyl groups.

The compounds of Formulae II, VII, X, XII, XIII, XV, XVII, XXXIV,XXXVII, XLIV, XLVIII, XLIX, LIII, LV, LVI, LIX, LXVI-LXXII, LXXV andLXXVI, and the reagents not designated by a Roman numeral are known or,if unkown, may be synthesized by processes analogous to those describedin the literature for similar known compounds.

The compounds of Formula XLI are also either known or, if unknown, maybe synthesized by processes analogous to those described in theliterature for the known compounds of said formula and similarcompounds. See, for example, Barton, Tetrahedron Letters 25, 3707-3710(1984), McKinnon, Canadian J. Chem. 43, 2628-2631 (1965), Patterson,Synthesis 1976, 281-304 and Sundberg, Comprehensive HeterocyclicChemistry, The Structure, Reactions, Synthesis and Uses of HeterocyclicCompounds, Vol. 4, Part 3, Bird et al. ed., Pergamon Press, Oxford(1984), pp. 313-374, and the references cited in each which are herebyincorporated by reference. A synthesis of the compounds of Formula XLIuseful for the synthesis of the preferred compounds of Formula I isdescribed in Reaction Scheme VII.

A preferred process for the synthesis of the erythro racemate of thecompound of Formula XXI wherein R₁₇ is hydrogen, R₁₉ is methyl, and X₃is a direct bond is disclosed in Kapa, Tetrahedron Letters 25, 2435-2438(1984). The other compounds of Formula XXI wherein R₁₇ is hydrogen, andX₃ is a direct bond in racemic erythro form may be synthesizedsimilarly. See also U.S. Pat. No. 4,571,428. Said patent, particularlycolumns 3-11 thereof, is hereby incorporated by reference.

The compounds of Formulae XXI and XXVI and their synthesis are disclosedin U.S. Pat. No. 4,613,610. Said patent, particularly columns 19-24,27-30 and 41-48 thereof, is hereby incorporated by reference.

Since any compound of Formula I wherein Z is a group of Formula awherein R₁₈ is a cation other than M may be converted into thecorresponding compound wherein R₁₈ is hydrogen, M or R₁₉ by theprocesses of Reaction Scheme IV, the compounds of Formula I wherein Z isa group of Formula a and R₁₈ is a pharmaceutically unacceptable cationare also within the scope of this invention since they are useful asintermediates. However, such compounds are not compounds of Formula I asutilized in this, except where indicated to the contrary.

Also within the scope of this invention are the intermediates ofFormulae III, IV, VIII, XI, XIV, XVI, XIX, XX, XXII, XXIV, XXVII, XXIX,XLV-XLVII and L-LII. The preferences for each variable are the same asthose set forth for the compounds of Formula I, with the preferredgroups of such compounds including those that correspond to Groups(xix)-(xxxvi) and (xlix)-(lx) (for Formulae XXVII and XXIX) and Groups(i)-(xviii) and (xxxvii)-(xlviii) (for each of the others) to the extentconsistent therewith.

The entire specification of parent application Ser. No. 06/791,198, nowabandoned, particularly pages 1-15, 23, 26, 41-44 and 51-53 thereof, ishereby incorporated by reference as if set forth herein in its entirety.

Besides having the utility set forth below, every compounf of Formula Iis useful as an intermediate in the synthesis of one or more othercompounds of Formula I utilizing the reactions set forth in ReactionScheme IV.

The compounds of Formula I are competitive inhibitors of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the ratelimiting enzyme in cholesterol biosynthesis, and, therefore, they areinhibitors of cholesterol biosynthesis. Consequently, they are usefulfor lowering the blood cholesterol level in animals, e.g., mammals,especially larger primates such as humans, and, therefore, ashypolipoproteinemic and anti-atherosclerotic agents. The biologicalactivity of the compounds of Formula I may be demonstrated in thefollowing tests:

Test A. In Vitro Microsomal Assay of HMG-CoA Reductase Inhibition:

This test is carried out precisely as described in column 53 of U.S.Pat. No. 4,613,610 and on page 30 of World (PCT) Published PatentApplication No. 84/02131, both of which are hereby incorporated byreference as if set forth herein in their entirety. The concentration ofthe test substance (compound of Formula I) in the assay system is0.0005-2,000 μmolar. The obtained IC₅₀ is the concentration of the testsubstance in the assay system observed or calculated to produce a 50%inhibition of HMG-CoA reductase activity.

Test B. In Vivo Cholesterol Biosynthesis Inhibition Test:

This test is carried out precisely as described in column 53 of saidU.S. Pat. No. 4,613,610 and on page 33 of World (PCT) Published PatentApplication No. 84/02131, both of which are hereby incorporated byreference as if set forth herein in their entirety. In this test therats are orally administered the test substance (compound of Formula I)at a dose of 0.1-200 mg/kg. body weight. The obtained ED₅₀ is the doseof the test substance observed or calculated to produce a 50% inhibitionof 3β-hydroxysterol synthesis.

In Test A, tested compounds of Formula I had IC₅₀ 's of 0.014-0.454μmolar whereas that of Compactin was 1.1 μmolar and that of Mevinolinwas 0.72 μmolar. The preferred compound of this application, that ofExample 2, had an IC₅₀ of 0.014 μmolar. In Test B, tested compounds ofFormula I had ED₅₀ 's of 0.53-0.97 mg/kg. whereas that of Compactin was3.5 mg./kg. and that of Mevinolin was 0.41 mg./kg. The ED₅₀ of thepreferred compound, that of Example 2, was 0.53 mg./kg.

Since they inhibit cholesterol biosynthesis, the compounds of Formula I(including those of each subgroup thereof) are useful for lowering theblood cholesterol level in animals, e.g., mammals, especially largerprimates, in particular humans, and, therefore, as hypolipoproteinemicand anti-atherosclerotic agents.

The precise dosage of the compound of Formula I to be employed forinhibiting cholesterol biosynthesis depends upon several factorsincluding the host, the nature and the severity of the condition beingtreated, the mode of administration and the particular active substance(compound of Formula I) employed. However, in general, suitable oraldaily dosages of the compounds of Formula I for the satisfactoryinhibition or reduction of cholesterol biosynthesis (i.e., thesatisfactory reduction of blood cholesterol level and satisfactorytreatment of hyperlipoproteinemia and atherosclerosis) are indicated bythe test data to be 0.06-100 mg./kg. body weight, e.g., 0.06-6 mg./kg.body weight for the more active compounds. For most larger primates suchas humans, a suitable oral daily dosage is indicated to be 4-2,000 mg.,e.g., 4-200 mg. for the more active compounds. The daily dosage of thecompound of Example 2 is indicated to be 4-200 mg., preferably 10-40mg., for most larger primates such as humans. For administration byinjection, a dosage somewhat lower than would be used for oraladministration of the same active substance to the same host having thesame condition is usually employed. However, the above dosages are alsotypically used for i.v. administration.

The daily dosage may be administered in a single dose but more typicallyis administered in two to four equal portions, typical doses being1-2,000 mg. Often, a small dosage is administered initially, and thedosage is gradually increased until the optimal dosage for the hostunder treatment is determined.

A typical dosage unit for oral administration may contain 1-500 mg. of acompound of Formula I.

The compounds of Formula I may be formulated into conventionalpharmaceutical compositions and administered by any conventional mode ofadministration, in particular enterally, e.g., in the form of capsulesor tablets, or parenterally, e.g., in the form of sterile injectablesolutions or suspensions. The pharmaceutical compositions comprise acompound of Formula I and at least one pharmaceutically acceptable solidor liquid carrier (or diluent). They may be formulated in conventionalmanner. The compounds of each subgroup thereof may likewise beformulated into such pharmaceutical compositions and administered bysuch routes.

The compounds of Formula I (including those of each subgroup thereof)may be formulated into such pharmaceutical compositions containing anamount of the active substance that is effective for inhibitingcholesterol biosynthesis in unit dosage form and such compositionscomprising at least one solid pharmaceutically acceptable carrier.

A representative formulation suitable for encapsulation in a hardgelatin capsule by conventional techniques is:

Compound of formula I, e.g., the compound of

    ______________________________________                                        Example 2         5 mg.                                                       Corn starch      244 mg.                                                      Magnesium stearate                                                                              1 mg.                                                       ______________________________________                                    

The following examples show representative compounds encompassed by thisinvention and their synthesis. However, it should be understood thatthey are for purposes of illustration only.

EXAMPLE 1 Ethyl(±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate##STR26## HHOH(CXIX)CHCH_(2OHCHCH) _(2COOC) ₂ H_(5F) ? Step 1 (ReactionCB) (2-Oxo-2-phenylethyl)triphenylphosphonium bromide (Compound CII)

50.0 g. (251 mmoles) of α-bromoacetophenone (Compound CI) and 65.9 g.(251 mmoles) of triphenylphosphine are stirred in 500 ml. of toluene at20°-25° C. under nitrogen for 16 hours, and the resulting solid iscollected by filtration, rinsed with toluene and rinsed with diethylether to obtain the product as a white powder (107.98 g. (93%)).

Step 2 (Reaction CC) (E)-4-Methyl-1-phenylpent-2-en-1-one (Compound CIV)

A solution of 6.64 g. (289 mmoles) of sodium in 250 ml. of absoluteethanol is quickly added dropwise to a suspension of 133.3 g. (289mmoles) of Compound CII in 1 l. of absolute ethanol stirred at 20°-25°C., the suspension is gently warmed until a clear solution results, 31.5ml. (25.0 g.; 347 mmoles) of isobutyraldehyde is added dropwise to thesolution, and the reaction mixture is refluxed for 16 hours and cooledto 20°-25° C., the reaction mixture being maintained under dry nitrogenthroughout. The reaction mixture is evaporated at reduced pressure, theresulting oily solid is triturated with diethyl ether, and the insolublematerial is removed by filtration. The diethyl ether solution is washedwith water, washed twice with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered and evaporated at reducedpressure. The residue is triturated with diethyl ether, any insolublematerial is removed by filtration, and the diethyl ether is evaporatedat reduced pressure to obtain a clear yellow liquid which isfractionally vacuum distilled through a vacuum jacketed Vigreux columnto obtain the product as a clear liquid (22.8 g.), b.p. 90°-92° C./˜1mm. Hg.

Step 3 (Reaction CE) Ethyl(±)-2-[1'-(1"-methylethyl)-2'-oxo-2'-phenylethyl]-1,3-dithiolane-2-carboxylate(Compound CVI)

83 ml. of 1.65M. n-butyllithium/hexane (138 mmoles) is added via syringeto a solution of 20.2 ml. (14.58 g.; 144 mmoles) of diisopropylamine in200 ml. of dry tetrahydrofuran (distilled from ketyl) stirred at -78°C., the reaction mixture is warmed to 0° C. and cooled to -78° C., 18.7ml. (23.35 g.; 131 mmoles) of ethyl 1,3-dithiolane-2-carboxylate(Compound CV) is added dropwise to the reaction mixture stirred at -78°C., the reaction mixture is stirred at -78° C. for 30 minutes, asolution of 22.749 g. (131 mmoles) of Compound CIV in 50 ml. of drytetrahydrofuran (distilled from ketyl) is added dropwise with stirringat -78° C., and the reaction mixture is stirred at -78° C. for 3 hours,the reaction mixture being maintained under dry nitrogen throughout. Thereaction mixture is quenched at -78° C. with saturated ammonium chloridesolution and warmed to 20°-25° C., the tetrahydrofuran is evaporated atreduced pressure, and the residue is partitioned between ethyl acetateand water. The aqueous phase is acidified to about pH 2 with 10%hydrochloric acid and extracted with ethyl acetate. The ethyl acetatelayers are combined, washed twice with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andevaporated at reduced pressure. The residue is triturated with diethylether to obtain the crude product as a white solid (27.13 g.).

Step 4 (Reaction CF) Ethyl(±)-2,5-dioxo-3-(1'-methylethyl)-5-phenylpentanoate (Compound CVII)

A solution of 27.1 g. (76.9 mmoles) of crude Compound CVI from Step 3 in200 ml. of acetonitrile is added dropwise to a solution of 82.1 g.(461.3 mmoles) of N-bromosuccinimide in 500 ml. of a 4:1 mixture ofacetonitrile and water stirred at 0° C., the reaction mixture is stirredat 0° C. for 4.5 hours, sufficient saturated sodium carbonate solutionis added to obtain a clear solution, the acetonitrile is evaporated atreduced pressure, the residue is partitioned between ethyl acetate andwater, the aqueous phase is acidified to about pH 2 with 10% aqueoushydrochloric acid and extracted with ethyl acetate, and the ethylacetate layers are combined, washed twice with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andevaporated at reduced pressure to obtain the crude product as a clearyellow liquid (23.49 g.).

Step 5 (Reaction CG) Ethyl1-(4'-fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxylate(Compound CIX)

24.59 g. (89 mmoles) of crude Compound CVII from Step 4 and 16.9 ml.(19.8 g.; 178 mmoles) of 4-fluoroaniline are stirred at 0° C. in 350 ml.of toluene, a solution of 5.9 ml. (10.13 g.; 53.4 mmoles) of titaniumtetrachloride in 50 ml. of hexane is added dropwise with stirring at 0°C., and the reaction mixture is allowed to slowly warm to 20°-25° C. andrefluxed for 16 hours, the reaction mixture being maintained under drynitrogen throughout. The reaction mixture is filtered through a pad ofCelite, the Celite is rinsed with ethyl acetate, and the rinse andfiltrate are combined and evaporated at reduced pressure to obtain abrown solid (25.1 g.). The brown solid is recrystallized from absoluteethanol to obtain slightly colored needles (16.74 g.), a second crop isobtained from the absolute ethanol (2.87 g.), and the two crops arecombined and recrystallized from absolute ethanol to obtain the productas a white powder (15.49 g.).

A small sample is dissolved in the minimum amount of methylene chlorideand flash chromatographed on 250 g. of 230-400 mesh A.S.T.M. silica gelutilizing 25% diethyl ether/hexane as the eluant, the eluant isevaporated, and the residue is recrystallized from absolute ethanol toobtain an analytical sample, m.p. 107°-110° C.

Step 6 (Reaction AA)1-(4'-Fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-methanol(Compound CX)

A solution of 15.0 g. (42.7 mmoles) of Compound CIX in 100 ml. of drytetrahydrofuran (distilled from ketyl) is added dropwise to a suspensionof 4.86 g. (128.1 mmoles) of lithium aluminum hydride in 150 ml. of drytetrahydrofuran (distilled from ketyl) stirred at 0° C., and thereaction mixture is allowed to warm to 20°-25° C., stirred at 20°-25° C.for 3 hours and cooled to 0° C., the reaction mixture being stirredunder dry nitrogen throughout. The reaction mixture is quenched at 0° C.with water, the white gum is removed by filtration, the small aqueousphase is separated and the organic phase is washed twice with saturatedsodium chloride solution, dried over anhydrous magnesium sulfate,filtered and evaporated at reduced pressure to obtain a white solid(12.59 g.) which is recrystallized from diethyl ether/hexane to obtainthe product as a white powder (6.58 g.). The mother liquor is evaporatedat reduced pressure, and the residue is recrystallized from methylenechloride/hexane to obtain a second crop (1.903 g.). Total yield: 8.48 g.(64%).

Revised procedure:

A solution of 29.6 g. (84.2 mmoles) of Compound CIX in 250 ml. of drydiethyl ether is added dropwise to a suspension of 9.6 g. (252.6 mmoles)of lithium aluminum hydride in 250 ml. of dry diethyl ether stirred at0° C. under dry nitrogen, and the reaction mixture is stirred at 0° C.under dry nitrogen for 2 hours. The reaction mixture is quenched at 0°C. with water and filtered. The filtrate is washed with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andevaporated at reduced pressure to obtain the crude product as a whitesolid (23.92 g. (92%)).

Step 7 (Reaction AB)1-(4'-Fluorophenyl)-3-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxaldehyde(Compound CXII)

A solution of 7.8 g. (25.2 mmoles) of Compound CX in 200 ml. of dryacetone (dried over 4Å. molecular sieves) is added dropwise to a mixtureof 483 mg. (0.5 mmole) of tris(triphenylphosphine)ruthenium(II) chloride(Compound CXI) and 8.62 g. (50.4 mmoles) ofN-methylmorpholine-N-oxide.monohydrate in 100 ml. of dry acetone (driedover 4Å. molecular sieves) stirred at 20°-25° C., and the reactionmixture is stirred at 20°-25° C. for 4 hours, the reaction mixture beingmaintained under dry nitrogen throughout. The reaction mixture isfiltered through 230-400 mesh A.S.T.M. silica gel, the silica gel isrinsed with diethyl ether, and the rinse and filtrate are combined andevaporated at reduced pressure to obtain a tan solid. The tan solid isdissolved in the minimum amount of methylene chloride and flashchromatographed on 450 g. of 230-400 mesh A.S.T.M. silica gel utilizing25% diethyl ether/hexane as the eluant, and the eluant is evaporated atreduced pressure to obtain the product as a flocculant white solid (5.3g. (68%)), m.p. 135°-139° C.

Revised procedure:

A solution of 24 g. (77.6 mmoles) of crude Compound CX (Step 6, revisedprocedure) in 250 ml. of dry acetone is added dropwise to a mixture of1.5 g. (1.6 mmoles) of Compound CXI and 18 g. (154 mmoles) ofN-Methylmorpholine-N-oxide.monohydrate in 250 ml. of dry acetone stirredat 20°-25° C., and the reaction mixture is stirred at 20°-25° C. for 4hours, the reaction mixture being maintained under dry nitrogenthroughout. 250 g. of 230-400 mesh A.S.T.M. silica gel is added, and theslurry is filtered through a 2 l. sintered glass funnel about one halffull of the same silica gel. The silica gel is washed with 2 l. of 25%diethyl ether/hexane, and the filtrate and washing are combined andevaporated at reduced pressure. The obtained flocculant yellow solid isrecrystallized from diethyl ether to obtain the product (13.12 g.).Additional product may be obtained from the mother liquor.

Step 8 (Reaction AF) Ethyl(E)-3-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-enoate(Compound CXIV)

1.03 g. of 60% sodium hydride/mineral oil (25.7 mmoles) is washed twicewith hexane and suspended in 100 ml. of dry tetrahydrofuran (distilledfrom ketyl), the suspension is stirred at 20°-25° C., approximately 1ml. of triethyl phosphonoacetate (Compound CXIII) is added to initiatethe reaction, the reaction mixture is cooled to -20°--15° C.,approximately 3.9 ml of triethyl phosphonoacetate is added dropwise withstirring at -20°--15° C. (the total amount of triethyl phosphonoacetatebeing 4.9 ml. (5.48 g.; 24.45 mmoles)), the reaction mixture is stirredat -20°--15° C. for 1 hour, a solution of 5.0 g. (16.3 mmoles) ofCompound CXII in 50 ml. of dry tetrahydrofuran (distilled from ketyl) isadded dropwise with stirring at -20°--15° C., and the reaction mixtureis allowed to warm to 20°-25° C., refluxed for 3 hours and stirred at20°-25° C. for 16 hours, the reaction mixture being maintained under drynitrogen throughout. The reaction mixture is diluted with diethyl etherand extracted with water, and the aqueous phase is reextracted withdiethyl ether. The organic phases are combined, washed twice withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and evaporated at reduced pressure to obtain a whitesolid which is recrystallized from diethyl ether to obtain the productas a white powder (4.877 g.). A second crop is obtained from diethylether/hexane (0.66 g.). Total yield: 5.54 g. (90%).

An analytical sample is obtained by recrystallization of a small samplefrom diethyl ether/hexane, m.p. 145°-147.5° C.

Step 9 (Reaction AG)(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-ol(Compound CXV)

44 ml. of 1.5M. diisobutylaluminum hydride/toluene (66 mmoles) is addeddropwise to a solution of 5.0 g. (13.25 mmoles) of Compound CXIV in 100ml. of dry tetrahydrofuran (distilled from ketyl) stirred at -78° C.,and the reaction mixture is stirred at -78° C. for 1 hour, the reactionmixture being stirred under dry nitrogen throughout. The reactionmixture is quenched at -78° C. with water and warmed to 20°-25° C.,sufficient 10% hydrochloric acid is added to dissolve the gel, and themixture is extracted twice with diethyl ether. The diethyl etherextracts are combined, washed with saturated sodium bicarbonatesolution, washed twice with saturated sodium chloride solution, driedover anhydrous magnesium sulfate, filtered and evaporated at reducedpressure. The residue is recrystallized from diethyl ether to obtain theproduct as a white powder (3.1 g.), m.p. 142°-148° C. The mother liquoris evaporated at reduced pressure, the residue is dissolved in theminimum amount of methylene chloride and flash chromatographed on 150 g.of 230-400 mesh A.S.T.M. silica gel utilizing 50% diethyl ether/hexaneas the eluant, and the eluant is evaporated at reduced pressure toobtain additional product as a tan powder (0.53 g.). Total yield: 3.63g. (82%).

Step 10 (Reaction AH)(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-al(Compound CXVI)

A solution of 3.3 g. (9.84 mmoles) of Compound CXV in 150 ml. of dryacetone (dried over 4Å. molecular sieves) is added dropwise to a mixtureof 283 mg. (0.3 mmole) of tris(triphenylphosphine)ruthenium(II) chloride(Compound CXI) and 2.31 g. (19.68 mmoles) ofN-methylmorpholine-N-oxide.monohydrate in 100 ml. of dry acetone (driedover 4Å. molecular sieves) stirred at 20°-25° C., the reaction mixtureis stirred at 20°-25° C. for 3 hours, an additional 1.15 g. (9.84mmoles) of N-methylmorpholine-N-oxide.monohydrate is added, the reactionmixture is stirred at 20°-25° C. for 2 hours, an additional 189 mg. (0.2mmole) of tris(triphenylphosphine)ruthenium(II) chloride is added, andthe reaction mixture is stirred at 20°-25° C. for 16 hours, the reactionmixture being stirred under dry nitrogen throughout. The reactionmixture is filtered through a pad of Celite and evaporated at reducedpressure to obtain a dark green oily solid which is dissolved in theminimum amount of methylene chloride and flash chromatographed on 250 g.of 230-400 mesh A.S.T.M. silica gel utilizing 25% diethyl ether/hexaneas the eluant. The eluant is evaporated at reduced pressure to obtainthe product as a yellow solid (2.49 g. (76%)), m.p. 180°-184° C.

Step 8A (Reaction AI)(E)-3-[1'-(4"-Fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-al(Compound CXVI)

29 ml. of 1.7M. t-butyllithium/pentane (49.3 mmoles) is added dropwiseto a solution of 2.6 ml. (3.72 g.; 24.6 mmoles) ofcis-1-bromo-2-ethoxyethylene in 50 ml. of dry tetrahydrofuran stirred at-78° C., the reaction mixture is stirred at -78° C. for 4 hours, asolution of 5.0 g. (16.3 mmoles) of Compound CXII in 25 ml. of drytetrahydrofuran is added dropwise with stirring at -78° C., and thereaction mixture is stirred at -78° C. for 45 minutes, the reactionmixture being maintained under dry nitrogen throughout. The reactionmixture is quenched with saturated ammonium chloride solution and warmedto 20°-25° C., the tetrahydrofuran is evaporated at reduced pressure,and the residue is partitioned between diethyl ether and water. Theaqueous phase is extracted with diethyl ether, and the two diethyl etherphases are combined, washed twice with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andevaporated to an orange gum at reduced pressure. The orange gum isdissolved in 100 ml. of a 9:1 mixture of tetrahydrofuran and water, 0.31g. (1.63 mmoles) of p-toluenesulfonic acid.monohydrate is added, thereaction mixture is stirred at 20°-25° C. for 4 hours, thetetrahydrofuran is evaporated at reduced pressure, and the residue ispartitioned between chloroform and water. The aqueous phase is extractedwith chloroform, and the chloroform phases are combined, washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and evaporated at reduced pressure to obtain a greensolid. The green solid is dissolved in the minimum amount of chloroform,adsorbed onto 25 g. of 230-400 mesh A.S.T.M. silica gel and flashchromatographed on 400 g. of the same silica gel utilizing 1:1 diethylether/hexane as the eluant. The eluant is evaporated at reduced pressureto obtain the crude product as an orange solid (4.28 g. (79%)).

Step 11 (Reaction A) Ethyl(±)-(E)-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]-5-hydroxy-3-oxohept-6-enoate(Compound CXVIII)

528 mg. (13.2 mmoles) of 60% sodium hydride/mineral oil is washed twicewith hexane, the sodium hydride is suspended in 50 ml. of drytetrahydrofuran (distilled from ketyl), the suspension is cooled to-20°--15° C., 1.53 ml. (1.56 g.; 12.0 mmoles) of ethyl acetoacetate isadded dropwise, the reaction mixture is stirred at -20°--15° C. for 30minutes, 7.6 ml. of 1.65M. n-butyllithium/hexane (12.54 mmoles) is addeddropwise with stirring at -20°--15° C., the reaction mixture is stirredat -20°--15° C. for 15 minutes, a solution of 2.0 g. (6.0 mmoles) ofCompound CXVI in 50 ml. of dry tetrahydrofuran (distilled from ketyl) isadded dropwise with stirring at -15° C., and the reaction mixture isstirred at -15° C. for 2.5 hours, the reaction mixture being stirredunder dry argon throughout. The reaction mixture is quenched at -15° C.with saturated ammonium chloride solution and warmed to 20°-25° C., thetetrahydrofuran is evaporated at reduced pressure, the residue ispartitioned between diethyl ether and water, the aqueous phase isextracted with diethyl ether, and the diethyl ether phases are combined,washed twice with saturated sodium chloride solution, dried overmagnesium sulfate, filtered and evaporated at reduced pressure to abrown oil. The brown oil is dissolved in the minimum amount of methylenechloride and flash chromatographed on 250 g. of 230-400 mesh A.S.T.M.silica gel utilizing 1:1 diethyl ether/hexane as the eluant, and theeluant is evaporated at reduced pressure to obtain the product as ayellow solid (2.51 g. (90%)).

A small sample is recrystallized from diethyl ether/hexane to obtain ananalytical sample, m.p. 98°-101° C.

Revised procedure:

1.16 g. of 60% sodium hydride/mineral oil (29 mmoles) is washed withhexane, the sodium hydride is suspended in 100 ml. of drytetrahydrofuran, the suspension is cooled to -20°-15° C., 3.3 ml. (3.37g.; 25.9 mmoles) of ethyl acetoacetate is added dropwise, the reactionmixture is stirred at -20°--15° C. for 30 minutes, 17 ml. of 1.6M.n-butyllithium/hexane (27.2 mmoles) is added dropwise with stirring at-20°--15° C., the reaction mixture is stirred at -20°--15° C. for 15minutes, a solution of 4.28 g. (12.8 mmoles) of crude Compound CXVI(from Step 8A) in 100 ml. of dry tetrahydrofuran is added dropwise withstirring at -20°--15° C. and the reaction mixture is stirred at-20°--15° C. for 30 minutes, the reaction mixture being stirred underdry nitrogen throughout. The reaction mixture is quenched with saturatedammonium chloride solution and warmed to 20°-25° C., the tetrahydrofuranis evaporated at reduced pressure, and the residue is partitionedbetween diethyl ether and water. The aqueous phase is extracted withdiethyl ether, and the diethyl ether phases are combined, washed twicewith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and evaporated at reduced pressure to obtain a darkorange oil. The dark orange oil is dissolved in the minimum amount ofmethylene chloride and flash chromatographed on 500 g. of 230-400 meshA.S.T.M. silica gel utilizing 1:1 diethyl ether/hexane as the eluant.The fractions containing relatively pure product (as determined by thinlayer chromatography) are combined and evaporated at reduced pressure toobtain the product as an oily solid (2.33 g.). The other fractionscontaining the product are combined, evaporated at reduced pressure,dissolved in the minimum amount of methylene chloride and flashchromatographed on 350 g. of 230-400 mesh A.S.T.M. silica gel utilizing,successively, 40%, 50% and 80% diethyl ether/hexane as the eluants. Thefractions containing the product are combined and evaporated at reducedpressure to obtain additional product as an orange oil that solidifiesupon standing (2.54 g.). Total yield: 4.87 g. (80.5%).

The product is a racemate which may be resolved to obtain the 5R and 5Senantiomers.

Step 12 (Reaction B) Ethyl(±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate(Compound CXIX)

(a) 4.32 ml. of 1.0M tri-n-butylborane/tetrahydrofuran (4.32 mmoles) isadded quickly dropwise to a solution of 1.0 g. (2.16 mmoles) of CompoundCXVIII in 25 ml. of dry tetrahydrofuran (distilled from ketyl) stirredat 20°-25° C., air is bubbled through the solution for 1 minute, thesolution is stirred at 20°-25° C. for 1 hour and cooled to -78° C., 408mg. (10.8 mmoles) of sodium borohydride is added with stirring at -78°C., and the reaction mixture is stirred at -50° C. for 16 hours andallowed to slowly warm to -20° C. to complete the reaction, the reactionmixture being stirred under dry nitrogen throughout. The reactionmixture is quenched at -20° C. with 10% hydrochloric acid (to pH 2),allowed to warm to 20°-25° C. and partitioned between diethyl ether andwater. The aqueous phase is extracted with diethyl ether, and theorganic phases are combined, washed twice with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andevaporated at reduced pressure to a clear yellow oil. A small amount ofisopropanol is added, and the isopropanol is evaporated at reducedpressure to obtain a yellow solid.

(b) The cyclic boron ester product of Part (a) is dissolved in methanolwith heating and the methanol is evaporated at reduced pressure, andthis procedure is repeated twice more to obtain a white solid which isrecrystallized from methylene chloride/hexane to obtain the product as aflocculant white solid (295.2 g. (29%)), m.p. 140°-142° C.

Revised procedure:

(a) 10.0 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (10.0 mmoles) isadded quickly dropwise to a solution of 2.33 g. (5.0 mmoles) of CompoundCXVIII (Step 11, revised procedure, first fraction) in 100 ml. of 4:1dry tetrahydrofuran/methanol stirred at 20°-25° C., air is bubbled infor 1 minute, the reaction mixture is stirred at 20°-25° C. for 1 hourand cooled to -78° C., 567 mg. (15.0 mmoles) of sodium borohydride isadded, and the reaction mixture is stirred at -78° C. for 2 hours, thereaction mixture being maintained under dry nitrogen throughout. Thereaction mixture is quenched at -78° C. with 4 ml. of acetic acid andwarmed to 20°-25° C., the solvent is evaporated at reduced pressure, andthe residue is partitioned between diethyl ether and water. The aqueousphase is extracted with diethyl ether, and the diethyl ether phases arecombined, washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered and evaporated at reduced pressureto obtain a yellow solid (3.31 g.).

(b) The cyclic boron ester product of Part (a) is dissolved in methanolwith heating and the methanol is evaporated at reduced pressure, andthis procedure is repeated twice more to obtain an oily yellow solidwhich is recrystallized from methylene chloride/hexane to obtain theproduct as a white powder, m.p. 144.5°-146.5° C.

The product is a mixture of the erythro and threo racemates wherein theratio of the former to the latter exceeds 9:1 (initial batch (m.p.140°-142° C.)) or 19:1 (revised procedure batch (m.p. 144.5°-146.5°C.)), which mixtures may be separated by conventional means. Theprincipal product, the erythro racemate, may be resolved into twooptically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of whichthe former is preferred. The minor product, the threo racemate, may beresolved to obtain the 3R,5R and 3S,5S enantiomers. The use of anon-stereoselective reduction would afford a mixture of all fourstereoisomers wherein the ratio of the erythro stereoisomers to thethreo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 2 Sodium(±)-erythro-(E)-3,5-dihydroxy-7-[1'-(4"-fluorophenyl)-3'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate##STR27##

0.1 ml. of 0.5N. sodium hydroxide solution (0.05 mmole) is quickly addeddropwise to a suspension of 25 mg. (0.054 mmole) of Compound CXIX in 5ml. of absolute ethanol, and the reaction mixture is stirred at 20°-25°C. for 2 hours, diethyl ether is added, and the pale yellow precipitatedproduct is collected, stirred in diethyl ether and collected byfiltration (18 mg. (77%)), m.p. 175°-185° C. (dec.) (yellows at 145°C.).

N.M.R. (CD₃ OD+CDCl₃): 1.21 (m, 6H), 1.60 (m, 2H), 2.29 (m, 2H), 3.12(m, 1H), 3.95 (m, 1H), 4.20 (m, 1H), 5.40 (dd (J₁ =15 Hz., J₂ =7.5 Hz.),1H), 6.22 (dd (J=15 Hz.), 1H), 6.30 (s, 1H), 7.08 (m, 9H)

Revised procedure:

19 ml. of 0.5N. sodium hydroxide solution (9.5 mmoles) is added dropwiseto a suspension of 4.67 g. (10.0 mmoles) of Compound CXIX (Example 1,Step 12, revised procedure) in about 200 ml. of absolute ethanol stirredat 20°-25° C., and the reaction mixture is stirred at 20°-25° C. for 3hours. The reaction mixture is concentrated at reduced pressure by aboutone third, and diethyl ether is added to obtain a pale yellow powder(3.7 g.). The powder is stirred in diethyl ether at 20°-25° C. for 30minutes, and the fine pale yellow product is collected by filtration.M.p. 203°-206° C. (dec.) Additional product is obtained from the motherliquors. The combined yield of this batch and a similar smaller one isabout 81%.

The product is a mixture of the erythro and threo racemates wherein theratio of the former to the latter exceeds 9:1 (initial batch (m.p.175°-185° C. (dec.))) or 19:1 (revised procedure batch (m.p. 203°-206°C. (dec.))), which mixtures may be separated by conventional means. Theprincipal product, the erythro racemate, may be resolved into twooptically pure enantiomers, the 3R,5S and 3S,5R enantiomers, of whichthe former is preferred. The minor product, the threo racemate, may beresolved to obtain the 3R,5R and 3S,5S enantiomers. The use of astarting material synthesized by using a non-stereoselective reductionin Step 12 of Example 1 would afford a mixture of all four stereoisomerswherein the ratio of the erythro stereoisomers to the threostereoisomers ranges from 3:2 to 2:3.

EXAMPLE 3 Ethyl(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate##STR28## Step 1 (Reaction CD)(E)-3-(4'-Fluorophenyl)-1-phenylprop-2-en-1-one (Compound CXXIII)

52.0 g. (433 mmoles) of acetophenone is added to a solution of 21.8 g.(545 mmoles) of sodium hydroxide in a mixture of 196 ml. of water and122.5 ml. of 95% ethanol stirred at 20°-25° C., the resulting suspensionis cooled to 0°-5° C., and 53.74 g. (433 mmoles) of 4-fluorobenzaldehydeis added portionwise, the temperature of the reaction mixture rising to20° C. during the addition. The solidified reaction mixture is kept at20°-25° C. for 3 hours and refrigerated for 16 hours. The solid iscollected by filtration, rinsed with about 2 l. of water until therinses are neutral, rinsed with 200 ml. of cold 95% ethanol andrecrystallized from 95% ethanol to obtain the product as yellow flakes(66.25 g. (68%)), m.p. 83°-86° C.

Step 2 (Reaction CE) Ethyl(±)-2-[1'-(4"-fluorophenyl)-3'-oxo-3'-phenylpropyl]-1,3-dithiolane-2-carboxylate(Compound CXXIV)

The product is obtained from 25.0 g. (110.5 mmoles) of Compound CXXIIIand 16 ml. (19.7 g.; 110.5 mmoles) of Compound CV utilizing 17 ml. (12.3g.; 121.5 mmoles) of diisopropylamine and 73.0 ml. of 1.6M.n-butyllithium/hexane (116.8 mmoles) substantially in accordance withthe process of Step 3 of Example 1, the principal difference being thatsubsequent to the evaporation of the tetrahydrofuran the residue ispartitioned between diethyl ether and water. The crude product isobtained as a viscous clear brown liquid (45.86 g. (100%)).

Step 3 (Reaction CF) Ethyl(±)-2,5-dioxo-3-(4'-fluorophenyl)-5-phenylpentanoate (Compound CXXV)

The product is obtained from 45.86 g. (≦110.5 mmoles) of crude CompoundCXXIV from Step 2 utilizing 118 g. (663 mmoles) of N-bromosuccinimidesubstantially in accordance with the process of Step 4 of Example 1, theprincipal difference being that the reaction mixture is stirred at 0° C.for 3 hours. The obtained cloudy brown viscous oil is chromatographed ona Waters Prep-500 HPLC utilizing a silica gel column, methylene chlorideas the eluant and a flow rate of 300 ml./min. The fractions containing asubstantial amount of product are combined and evaporated at reducedpressure to obtain the crude product (16.33 g.).

Step 4 (Reaction CG) Ethyl3-(4'-fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxylate(Compound CXXVII)

The product is obtained from 16.33 g. (≦49.7 mmoles) of crude CompoundCXXV from Step 3 and 15 ml. (10.28 g.; 173.95 mmoles) of isopropylamineutilizing 30 ml. of 1.0M. titanium tetrachloride/hexane (30 mmoles)substantially in accordance with the process of Step 5 of Example 1, theprincipal difference being that the reaction mixture is stirred at20°-25° C. for 30 minutes prior to being refluxed. The obtained viscousorange oil solidifies upon standing, and the obtained solid isrecrystallized from absolute ethanol to obtain the product as whiteneedles (6.25 g. (36%)). A previous batch melted at 97°-100° C.

Step 5 (Reaction AA)3-(4'-Fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-methanol(Compound CXXVIII)

The product is obtained from 6.25 g. (17.8 mmoles) of Compound CXXVIIutilizing 2.0 g. (53.4 mmoles) of lithium aluminum hydride substantiallyin accordance with the process of Step 6 of Example 1, the principaldifference being that the reaction mixture is stirred at 0° C. for 1hour and at 20°-25° C. for 2 hours. The obtained white powder isrecrystallized from diethyl ether/hexane to obtain the product as awhite powder (4.83 g. (88%)).

Step 6 (Reaction AB)3-(4'-Fluorophenyl)-1-(1'-methylethyl)-5-phenyl-1H-pyrrole-2-carboxaldehyde(Compound CXXIX)

The product is obtained from 9.5 g. (30.7 mmoles) of Compound CXXVIIIutilizing 589 mg. (0.61 mmole) of tris(triphenylphosphine)ruthenium(II)chloride and 10.51 g. (61.4 mmoles) ofN-methylmorpholine-N-oxide.monohydrate substantially in accordance withthe process of Step 7 of Example 1, the principal difference being thatthe reaction mixture is stirred at 20°-25° C. for just 1 hour. Theobtained brown solid is dissolved in diethyl ether, the insolublematerial is removed by filtration, the diethyl ether is evaporated atreduced pressure to obtain a white solid, and the white solid isrecrystallized from diethyl ether to obtain the product as a whitepowder (7.43 g.), m.p. 118°-122° C. A second crop is also obtained (0.84g.).

Step 7 (Reaction AF) Ethyl(E)-3-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-enoate(Compound CXXX)

The product is obtained from 7.3 g. (24 mmoles) of Compound CXXIX and7.2 ml. (8.07 g.; 36 mmoles) of triethyl phosphonoacetate utilizing 1.51g. (37.8 mmoles) of 60% sodium hydride/mineral oil substantially inaccordance with the process of Step 8 of Example 1, the principaldifferences being that the reaction mixture is refluxed for 4 hours andthe stirring at 20°-25° C. for 16 hours is omitted. The obtained yellowoil solidifies upon standing, and the resulting solid is recrystallizedfrom diethyl ether/hexane to obtain the product as a yellow powder (6.46g. (71%)), m.p. 84°-87° C.

Step 8 (Reaction AG)(E)-3-[3'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-ol(Compound CXXXI)

The product is obtained from 6.3 g. (17 mmoles) of Compound CXXXutilizing 45 ml. of 1.5M. diisobutylaluminum hydride/toluene (67.5mmoles) substantially in accordance with the process of Step 9 ofExample 1, the principal difference being that the reaction is carriedout at 0° C. for 2 hours. However, the use of a lower reactiontemperature, e.g., -78° C., should give a much better yield of theproduct.

Step 9 (Reaction AH)(E)-3-[3'-(4"-Fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]prop-2-en-1-al(Compound CXXXII)

The product is obtained from 200 mg. (0.6 mmole) of Compound CXXXIutilizing 14 mg. (0.015 mmole) of tris(triphenylphosphine)ruthenium(II)chloride and 14 mg. (1.2 mmoles) ofN-methylmorpholine-N-oxide.monohydrate substantially in accordance withthe process of Step 10 of Example 1, the principal differences beingthat no additional N-methylmorpholine-N-oxide.monohydrate is added, thesecond batch (14 mg.; 0.015 mmole) of the ruthenium salt is added after2 hours at 20°-25° C., and 1:1 diethyl ether/hexane is utilized as theeluant in the flash chromatography. The product is obtained as a brightyellow foam.

Step 10 (Reaction A) Ethyl(±)-(E)-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]-5-hydroxy-3-oxohept-6-enoate(Compound CXXXIII)

The product is obtained from 581 mg. (1.74 mmoles) of Compound CXXXIIand 0.44 ml. (454 mg.; 3.48 mmoles) of ethyl acetoacetate utilizing 153mg. of 60% sodium hydride/mineral oil (3.83 mmoles) and 2.2 ml. of1.65M. n-butyllithium/hexane (3.63 mmoles) substantially in accordancewith the process of Step 11 of Example 1, the principal differencesbeing that the reaction mixture is stirred at -20°--15° C. for 15minutes prior to the addition of the n-butyllithium/hexane and for just10 minutes subsequent to the addition of Compound CXXXII, and 60%diethyl ether/hexane is used as the eluant in the flash chromatography.The product is obtained as a viscous yellow oil (545.3 mg.).

The product is a racemate that may be resolved by conventional means toobtain the 5R and 5S enantiomers.

Step 11 (Reaction B) Ethyl(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate(Compound CXXXIV)

(a) 1.18 ml. of 1.0M. tri-n-butylborane/tetrahydrofuran (1.18 mmoles) isquickly added dropwise to a solution of 273.2 mg. (0.59 mmole) ofCompound CXXXIII in 5 ml. of dry tetrahydrofuran (distilled from ketyl)stirred at 20°-25° C., air is bubbled into the reaction mixture for 1minute, the reaction mixture is stirred at 20°-25° C. for 1 hour andcooled to -78° C., 56 mg. (1.475 mmoles) of sodium borohydride is addedwith stirring at -78° C., the reaction mixture is stirred at -50° C. for16 hours, an additional 56 mg. (1.475 mmoles) of sodium borohydride isadded with stirring at -50° C., and the reaction mixture is allowed toslowly warm to -10° C. and is stirred at -10° C. for 1 hour, thereaction mixture being maintained under dry nitrogen throughout. Thereaction mixture is quenched at -10° C. with 10% hydrochloric acid (topH 2), warmed to 20°-25° C. and partitioned between diethyl ether andwater, and the aqueous phase is extracted with diethyl ether. Thediethyl ether phases are combined, washed twice with saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered andevaporated at reduced pressure to obtain the cyclic boron ester as aclear yellow liquid.

(b) The cyclic boron ester product of Part (a) is dissolved in methanolwith gentle heating and the methanol is evaporated at reduced pressure,this process is repeated twice more, and the obtained yellow oil isdissolved in the minimum amount of methylene chloride and flashchromatographed on 150 g. of 230-400 mesh A.S.T.M. silica gel utilizing80% diethyl ether/hexane and then diethyl ether as the eluants.Evaporation of the eluant yields the product as a clear geen oil (166.1mg.).

N.M.R. (CDCl₃): 1.28 (t, 3H), 1.50 (d, 6H), 1.60 (m, 2H), 2.48 (m, 2H),3.28 (m, 1H), 3.71 (m, 1H), 4.20 (m, 3H), 4.46 (m, 1H), 4.59 (m, 1H),5.56 (dd, (J₁ =15 Hz., J₂ =5 Hz.), 1H), 6.14 (s, 1H), 6.75 (d, (J=15Hz.), 1H), 7.00 (t, 2H), 7.39 (m, 7H)

The product is a mixture of the erythro and threo racemates wherein theratio of the former to the latter is about 3:1, which mixture may beseparated by conventional means. The principal product, the erythroracemate, may be resolved into two optically pure enantiomers, the 3R,5Sand 3S,5R enantiomers, of which the former is preferred. The minorproduct, the threo racemate, may be resolved to obtain the 3R,5R and3S,5S enantiomers. The use of a non-stereoselective reduction wouldafford a mixture of all four stereoisomers wherein the ratio of theerythro stereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

EXAMPLE 4 Ethyl(±)-erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate##STR29##

A mixture of 120.4 mg. (0.26 mmole) of Compound CXXXIV, 24 mg. (0.39mmole) of boric acid and 5 ml. of isopropanol is stirred at 80° C. for 3hours, cooled to 20°-25° C. and evaporated at reduced pressure to obtaina yellow oil. The yellow oil is dissolved in isopropanol with warming,the isopropanol is evaporated at reduced pressure to obtain a yellowfoam, the yellow foam is dissolved in the minimum amount of hotisopropanol, the solution is stored at 0° C. for 16 hours, and themother liquor is decanted. The residual yellow wax is dissolved inmethanol with gentle heating and the methanol is evaporated at reducedpressure and this process is repeated twice to obtain a clear yellowoil. The oil is crystallized from methylene chloride/hexane to obtainthe product as a flocculant white solid (29.5 mg.), m.p. 105°-107° C.

The product is a mixture of the erythro and threo racemates wherein theratio of the former to the latter exceeds 9:1, which mixture may beseparated by conventional means. The principal product, the erythroracemate, may be resolved into two optically pure enantiomers, the 3R,5Sand 3S,5R enantiomers, of which the former is preferred.

EXAMPLE 5 Sodium(±)-erythro-(E)-3,5-dihydroxy-7-[3'-(4"-fluorophenyl)-1'-(1"-methylethyl)-5'-phenyl-1H-pyrrol-2'-yl]hept-6-enoate##STR30##

0.08 ml. of 0.5N. sodium hydroxide solution (0.04 mmole) is addeddropwise to a solution of 20 mg. (0.043 mmole) of Compound CXXXV in 2ml. of absolute ethanol stirred at 20°-25° C., the reaction mixture isstirred at 20°-25° C. for 2 hours, the ethanol is evaporated at reducedpressure, the residue is dissolved in water, and the obtained solutionis extracted with diethyl ether and lyophilized for 16 hours to obtainthe product as a white powder (16.8 mg.), m.p. 185°-192° C. (dec.)(changes color at 135° C.)

N.M.R. (CD₃ OD+CDCl₃): 1.48 (m, 6H), 1.64 (m, 2H), 2.30 (m, 2H), 4.00(m, 1H), 4.34 (m, 1H), 4.55 (m, 1H), 5.50 (dd (J₁ =15 Hz., J₂ =7.5 Hz.),1H), 6.02 (s, 1H), 6.71 (d (J=15 Hz.), 1H), 7.00 (t, (J=10 Hz.), 2H),7.38 (m, 7H)

The product is a mixture of the erythro and threo racemates wherein theratio of the former to the latter exceeds 9:1, which mixture may beseparated by conventional means. The principal product, the erythroracemate, may be resolved into two optically pure enantiomers, the 3R,5Sand 3S,5R enantiomers, of which the former is preferred. The minorproduct, the threo racemate, may be resolved to obtain the 3R,5R and3S,5S enantiomers. The use of a starting material synthesized by using anon-stereoselective reduction in Step 11 of Example 3 would afford amixture of all four stereoisomers wherein the ratio of the erythrostereoisomers to the threo stereoisomers ranges from 3:2 to 2:3.

Throughout the specification, the term "reduced pressure" denotesaspirator pressure. Where no solvent is specified in connection with asolution, the solvent is water, and all solvent mixtures are by volume.When a reaction is carried out under nitrogen, dry nitrogen is used tomaintain anhydrous conditions (except where the reaction medium containswater).

All nuclear magnetic resonance spectra were taken at ambient temperatureon a 200 MHz. spectrometer. All chemical shifts are given in p.p.m. (δ)relative to tetramethylsilane, and where a single δ value is given foranything other than a sharp singlet, it is its center point. In theN.M.R. data:

d=doublet

dd=doublet of a doublet

m=multiplet

s=singlet

t=triplet

Each of the compounds of the examples wherein Z is a group of Formula awherein R₁₈ is a cation may be converted into the correspondingcompounds wherein R₁₈ is hydrogen or a different cation M, particularlythe latter, especially M', by the processes set forth in Reaction SchemeIV.

Each of the compounds of Examples 1-5 (including each of the possibleisomers of the examples) may be administered to an animal, e.g., alarger primate, to inhibit cholesterol biosynthesis and thereby lowerthe blood cholesterol level for, for example, the treatment ofatherosclerosis and hyperlipoproteinemia. The dosages are those setforth supra.

What is claimed is:
 1. A compound of the formula ##STR31## wherein R₁ isC₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or##STR32## R₂ is C₁₋₆ alkyl not containing an assymetric carbon atom,C₃₋₇ cycloalkyl or ##STR33## R₃ is hydrogen, C₁₋₆ alkyl not containingan asymmetric carbon atom, C₃₋₇ cycloalkyl or ##STR34## R₄ is hydrogen,C₁₋₆ alkyl not containing an asymmetric carbon atom, C₃₋₇ cycloalkyl or##STR35## X is --(CH₂)_(m) --, --CH═CH--, --CH═CH--CH₂ -- or --CH₂--CH═CH--, wherein m is 0, 1, 2 or 3, andZ is ##STR36## wherein R₁₇ ishydrogen or C₁₋₃ alkyl, and R₁₈ is hydrogen, R₁₉ or M, wherein R₁₉ is aphysiologically acceptable ester group, and M is a cation,wherein eachof R₅, R₈, R₁₁ and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl,i-butyl, t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl,fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆, R₉, R₁₂and R₁₅ is independently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy,trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and eachof R₇, R₁₀, R₁₃ and R₁₆ is independently hydrogen, C₁₋₂ alkyl, C₁₋₂alkoxy, fluoro or chloro, with the provisos that not more than onesubstituent on each of Rings A, B, C and D independently istrifluoromethyl, not more than one substituent on each of Rings A, B, Cand D independently is phenoxy, and not more than one substituent oneach of Rings, A, B, C, and D independently is benzyloxy, with theprovisos that (i) the --X--Z group is in the 2- or 3-position of thepyrrole ring, (ii) the --X--Z group is ortho to both R₁ and R₂, and(iii) R₃ is ortho to R₂.
 2. A compound according to claim 1 wherein M isa pharmaceutically acceptable cation.
 3. A compound according to claim 2wherein R₁₉ is a physiologically acceptable and hydrolyzable estergroup.
 4. A compound according to claim 3 wherein R₁₉ is C₁₋₃ alkyl,n-butyl, i-butyl, t-butyl or benzyl.
 5. A compound according to claim 2having the formula ##STR37##
 6. A compound according to claim 5 whereinZ is ##STR38## wherein R₁₇ is hydrogen or C₁₋₃ alkyl, and R₁₈ ishydrogen, R₁₉ ' or M, wherein R₁₉ ' is C₁₋₃ alkyl, n-butyl, i-butyl,t-butyl or benzyl, andM is a pharmaceutically acceptable cation.
 7. Acompound according to claim 6 wherein R₁ is ##STR39## R₂ is C₁₋₆ alkylnot containing an asymmetric carbon atom, R₃ is hydrogen or C₁₋₆ alkylnot containing an asymmetric carbon atom,R₄ is ##STR40## R₁₇ is hydrogenor methyl, R₁₈ is hydrogen, R₁₉ ' or M, wherein R₁₉ ' is C₁₋₃ alkyl,n-butyl, i-butyl, t,butyl or benzyl, and M is a pharmaceuticallyacceptable cation, and X is --CH₂ CH₂ -- or --CH═CH--,wherein each of R₅and R₁₄ is independently hydrogen, C₁₋₃ alkyl, n-butyl, i-butyl,t-butyl, C₁₋₃ alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro,chloro, bromo, phenyl, phenoxy or benzyloxy, each of R₆ and R₁₅ isindependently hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, trifluoromethyl,fluoro, chloro, bromo, phenoxy or benzyloxy, and each of R₇ and R₁₆ isindependently hydrogen, C₁₋₂ alkyl, C₁₋₂ alkoxy, fluoro or chloro, withthe provisos that not more than one substituent on each of Rings A and Dindependently is trifluoromethyl, not more than one substituent on eachof Rings A and D independently is phenoxy, and not more than onesubstituent on each of Rings A and D independently is benzyloxy.
 8. Acompound according to claim 7 wherein R₂ is C₁₋₄ alkyl not containing anasymmetric carbon atom,R₃ is hydrogen or C₁₋₂ alkyl, each of R₅ and R₁₄is independently hydrogen, C₁₋₃ alkyl, C₁₋₂ alkoxy, trifluoromethyl,fluoro or chloro, each of R₆ and R₁₅ is independently hydrogen, C₁₋₂alkyl, fluoro or chloro each of R₇ and R₁₆ is independently hydrogen ormethyl, R₁₇ is hydrogen, R₁₈ is hydrogen, C₁₋₃ alkyl or M, wherein M isa pharmaceutically acceptable cation, and X is (E)--CH═CH--.
 9. Acompound according to claim 8 wherein R₃ is hydrogen or methyl, each ofR₅ and R₁₄ is independently hydrogen, methyl or fluoro, each of R₆ andR₁₅ is independently hydrogen or methyl,R₇ is hydrogen, R₁₆ is hydrogen,and R₁₈ is hydrogen, C₁₋₂ alkyl or M, wherein M is a pharmaceuticallyacceptable cation.
 10. A compound according to claim 9 wherein thehydroxy groups in the 3- and 5-positions have the erythro configuration.11. A compound according to claim 10 having the formula ##STR41##wherein M.sup.⊕ is a pharmaceutically acceptable cation.
 12. Thecompound according to claim 11 wherein M.sup.⊕ is sodium.
 13. A compoundaccording to claim 5 wherein Z is ##STR42##
 14. A compound according toclaim 2 having the formula ##STR43##
 15. A compound according to claim 2wherein X is --CH═CH--, --CH═CH--CH₂ -- or --CH₂ --CH═CH--.
 16. Acompound according to claim 15 wherein X is --CH═CH--.
 17. A compoundaccording to claim 16 wherein X is (E)--CH═CH--.
 18. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 2 and a pharmaceutically acceptable carrier, said effective amountbeing an amount effective for inhibiting cholesterol biosynthesis in amammal.
 19. A method of inhibiting cholesterol biosynthesis comprisingadministering to a mammal in need of such treatment an effective amountof a compound according to claim 2, said effective amount being anamount effective for inhibiting cholesterol biosynthesis.
 20. A methodof treating atherosclerosis comprising administering to a mammal in needof such treatment an effective amount of a compound according to claim2, said effective amount being an amount effective for the treatment ofatherosclerosis.
 21. A method of treating atherosclerosis according toclaim 20 comprising administering to a mammal in need of such treatmentan effective amount of a compound of the formula ##STR44## saideffective amount being an amount effective for the treatment ofatherosclerosis.
 22. A method of treating atherosclerosis according toclaim 21 comprising administering to a mammal in need of such treatmentan effective amount of a compound of the formula ##STR45##